Pharmaceutical compositions and methods for use

ABSTRACT

Patients susceptible to or suffering from conditions and disorders, such as central nervous system disorders, are treated by administering to a patient in need thereof aryloxyalkylamines, including pyridyloxylalkylamines and phenoxyalkylamines. Exemplary compounds include dimethyl(2-(3-pyridyloxy)ethylamine, dimethyl(4-(3-pyridyloxy)butyl)amine, 2-(3-pyridyloxy)ethylamine, 4-(3-pyridyloxy)butylamine, methyl(3-(5-methoxy-3-pyridyloxy)propyl)amine, ethyl(3-(3-pyridyloxy)propyl)amine, methyl(2-(3-pyridyloxy)ethyl)amine, methyl(3-(6-methyl(3-pyridyloxy))propyl)amine, (3-(3-methoxyphenoxy)propyl)methylamine, (3-(5-chloro(3-pyridyloxy))-1-methylpropyl)methylamine, dimethyl(3-(3-pyridyloxy)propyl)amine, 3-(3-pyridyloxy)propylamine, methyl(4-(3-pyridyloxy)butyl)amine, 3-(5-chloro-3-pyridyloxy)propyl amine, methyl(3-(5-isopropoxy-3-pyridyloxy)propyl)amine, (3-(5-chloro(3-pyridyloxy))propyl) methylamine, methyl(3-(5-(phenylmethoxy)(3-pyridyloxy))propyl)amine, methyl(3-(2-methyl(3-pyridyloxy))propyl)amine, (methylethyl)(3-(3-pyridyloxy)propyl)amine, benzyl(3-(3-pyridyloxy)propyl)amine, cyclopropyl(3-(3-pyridyloxy)-propyl)amine, methyl(1-methyl-3-(3-pyridyloxy)propyl)amine, methyl(3-(3-nitrophenoxy)propyl)amine, 1-(3-chloropropoxy)-3-nitrobenzene, (3-(3-aminophenoxy)propyl)methylamine,dimethyl (3-(3-(methylamino)-propoxy)phenyl)amine, methyl(3-tricyclo[7.3.1.0&lt;5,13&gt;]tridec-2-yloxypropyl)amine, (3-benzo[3,4-d]1,3-dioxolan-5-yloxypropyl)methylamine, 3-(4-piperidinyloxy)pyridine and 3-((3S)-3-pyrrolidinyloxy)pyridine.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This is a continuation-in-part of U.S. patent application Ser.No. 09/054,130, filed Apr. 2, 1998, the disclosure of which isincorporated herein in its entirety by reference.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to pharmaceutical compositions, andparticularly pharmaceutical compositions incorporating compounds thatare capable of affecting nicotinic cholinergic receptors. Moreparticularly, the present invention relates to compounds capable ofactivating nicotinic cholinergic receptors, for example, as agonists ofspecific nicotinic receptor subtypes. The present invention also relatesto methods for treating a wide variety of conditions and disorders, andparticularly conditions and disorders associated with dysfunction of thecentral and autonomic nervous systems.

[0003] Nicotine has been proposed to have a number of pharmacologicaleffects. See, for example, Pullan et al. N. Engl. J. Med. 330:811-815(1994). Certain of those effects may be related to effects uponneurotransmitter release. See for example, Sjak-shie et al., Brain Res.624:295 (1993), where neuroprotective effects of nicotine are proposed.Release of acetylcholine and dopamine by neurons upon administration ofnicotine has been reported by Rowell et al., J. Neurochem. 43:1593(1984); Rapier et al., J. Neurochem. 50:1123 (1988); Sandor et al.,Brain Res. 567:313 (1991) and Vizi, Br. J. Pharmacol. 47:765 (1973).Release of norepinephrine by neurons upon administration of nicotine hasbeen reported by Hall et al., Biochem. Pharmacol. 21:1829 (1972).Release of serotonin by neurons upon administration of nicotine has beenreported by Hery et al., Arch. Int. Pharmacodyn. Ther. 296:91 (1977).Release of glutamate by neurons upon administration of nicotine has beenreported by Toth et al., Neurochem Res. 17:265 (1992). In addition,nicotine reportedly potentiates the pharmacological behavior of certainpharmaceutical compositions used for the treatment of certain disorders.See, Sanberg et al., Pharmacol. Biochem. & Behavior 46:303 (1993);Harsing et al., J. Neurochem. 59:48 (1993) and Hughes, Proceedings fromIntl. Symp. Nic. S40 (1994). Furthermore, various other beneficialpharmacological effects of nicotine have been proposed. See, Decina etal., Biol. Psychiatry 28:502 (1990); Wagner et al., Pharmacopsychiatry21:301 (1988); Pomerleau et al., Addictive Behaviors 9:265 (1984);Onaivi et al., Life Sci. 54(3):193 (1994); Tripathi et al., JPET 221:91-96 (1982) and Hamon, Trends in Pharmacol. Res. 15:36.

[0004] Various nicotinic compounds have been reported as being usefulfor treating a wide variety of conditions and disorders. See, forexample, Williams et al. DN&P 7(4):205-227 (1994), Arneric et al., CNSDrug Rev. 1(1):1-26 (1995), Arneric et al., Exp. Opin. Invest. Drugs5(1):79-100 (1996), Bencherif et al., JPET 279:1413 (1996), Lippiello etal., JPET 279:1422 (1996), Damaj et al., Neuroscience (1997), Holladayet al., J. Med. Chem 40(28): 4169-4194 (1997), Bannon et al., Science279: 77-80 (1998), PCT WO 94/08992, PCT WO 96/31475, PCT WO 96/40682,and U.S. Pat. Nos. 5,583,140 to Bencherif et al., 5,597,919 to Dull etal. 5,604,231 to Smith et al. and 5,852,041 to Cosford et al. Nicotiniccompounds are reported as being particularly useful for treating a widevariety of Central Nervous System (CNS) disorders.

[0005] CNS disorders are a type of neurological disorder. CNS disorderscan be drug induced; can be attributed to genetic predisposition,infection or trauma; or can be of unknown etiology. CNS disorderscomprise neuropsychiatric disorders, neurological diseases and mentalillnesses; and include neurodegenerative diseases, behavioral disorders,cognitive disorders and cognitive affective disorders. There are severalCNS disorders whose clinical manifestations have been attributed to CNSdysfunction (i.e., disorders resulting from inappropriate levels ofneurotransmitter release, inappropriate properties of neurotransmitterreceptors, and/or inappropriate interaction between neurotransmittersand neurotransmitter receptors). Several CNS disorders can be attributedto a cholinergic deficiency, a dopaminergic deficiency, an adrenergicdeficiency and/or a serotonergic deficiency. CNS disorders of relativelycommon occurrence include presenile dementia (early onset Alzheimer'sdisease), senile dementia (dementia of the Alzheimer's type),Parkinsonism including Parkinson's disease, Huntington's chorea, tardivedyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety,dyslexia, schizophrenia and Tourette's syndrome.

[0006] It would be desirable to provide a useful method for theprevention and treatment of a condition or disorder by administering anicotinic compound to a patient susceptible to or suffering from such acondition or disorder. It would be highly beneficial to provideindividuals suffering from certain disorders (e.g., CNS diseases) withinterruption of the symptoms of those disorders by the administration ofa pharmaceutical composition containing an active ingredient havingnicotinic pharmacology and which has a beneficial effect (e.g., upon thefunctioning of the CNS), but which does not provide any significantassociated side effects. It would be highly desirable to provide apharmaceutical composition incorporating a compound which interacts withnicotinic receptors, such as those which have the potential to effectthe functioning of the CNS, but which compound when employed in anamount sufficient to effect the functioning of the CNS, does notsignificantly effect those receptor subtypes which have the potential toinduce undesirable side effects (e.g., appreciable activity at skeletalmuscle sites).

SUMMARY OF THE INVENTION

[0007] The present invention relates to aryloxyalkylamines, includingpyridyloxylalkylamines and phenoxyalkylamines. Exemplary compoundsinclude dimethyl(2-(3-pyridyloxy)ethylamine, dimethyl(4-(3-pyridyloxy)butyl)amine, 2-(3-pyridyloxy)ethylamine, 4-(3-pyridyloxy)butylamine,methyl(3-(5-methoxy-3-pyridyloxy)propyl)amine,ethyl(3-(3-pyridyloxy)propyl)amine, methyl(2-(3-pyridyloxy)ethyl)amine,methyl(3-(6-methyl(3-pyridyloxy))propyl)amine,(3-(3-methoxyphenoxy)propyl)methylamine,(3-(5-chloro(3-pyridyloxy))-1-methylpropyl)methylamine,dimethyl(3-(3-pyridyloxy)propyl)amine, 3-(3-pyridyloxy)propylamine,methyl(4-(3-pyridyloxy)butyl)amine,3-(5-chloro-3-pyridyloxy)propylamine,methyl(3-(5-isopropoxy-3-pyridyloxy)propyl)amine,(3-(5-chloro(3-pyridyloxy))propyl)methylamine,methyl(3-(5-(phenylmethoxy)(3-pyridyloxy))propyl)amine,methyl(3-(2-methyl(3-pyridyloxy))propyl)amine,(methylethyl)(3-(3-pyridyloxy)propyl)amine,benzyl(3-(3-pyridyloxy)propyl)amine,cyclopropyl(3-(3-pyridyloxy)propyl)amine,methyl(1-methyl-3-(3-pyridyloxy)propyl)amine,methyl(3-(3-nitrophenoxy)propyl)amine,1-(3-chloropropoxy)-3-nitrobenzene,(3-(3-aminophenoxy)propyl)methylamine,dimethyl(3-(3-(methylamino)-propoxy)phenyl)amine, methyl(3-tricyclo[7.3.1.0<5,13 >]-tridec-2-yloxypropyl)amine, (3-benzo[3,4-d]1,3-dioxolan-5-yloxypropyl)methylamine,3-(4-piperidinyloxy)pyridine, 3-((3S)-3-pyrrolidinyloxy)pyridine,(2-(5-bromo(3-pyridylthio))ethyl)methylamine,(2-(5-bromo(3-pyridylthio)) isopropyl)-methylamine,(2-(5-bromo(3-pyridylthio))-propyl)methylamine and(3-(5-bromo(3-pyridylthio))propyl)-methylamine. The present inventionalso relates to prodrug derivatives of the compounds of the presentinvention.

[0008] The present invention also relates to methods for the preventionor treatment of a wide variety of conditions or disorders, andparticularly those disorders characterized by disfunction of nicotiniccholinergic neurotransmission including disorders involvingneuromodulation of neurotransmitter release, such as dopamine release.The present invention also relates to methods for the prevention ortreatment of disorders, such as central nervous system (CNS) disorders,which are characterized by an alteration in normal neurotransmitterrelease. The present invention also relates to methods for the treatmentof certain conditions (e.g., a method for alleviating pain). The methodsinvolve administering to a subject an effective amount of a compound ofthe present invention.

[0009] The present invention, in another aspect, relates to apharmaceutical composition comprising an effective amount of a compoundof the present invention. Such a pharmaceutical composition incorporatesa compound which, when employed in effective amounts, has the capabilityof interacting with relevant nicotinic receptor sites of a subject, andhence has the capability of acting as a therapeutic agent in theprevention or treatment of a wide variety of conditions and disorders,particularly those disorders characterized by an alteration in normalneurotransmitter release. Preferred pharmaceutical compositions comprisecompounds of the present invention.

[0010] The pharmaceutical compositions of the present invention areuseful for the prevention and treatment of disorders, such as CNSdisorders, which are characterized by an alteration in normalneurotransmitter release. The pharmaceutical compositions providetherapeutic benefit to individuals suffering from such disorders andexhibiting clinical manifestations of such disorders in that thecompounds within those compositions, when employed in effective amounts,have the potential to (i) exhibit nicotinic pharmacology and affectrelevant nicotinic receptors sites (e.g., act as a pharmacologicalagonist to activate nicotinic receptors), and (ii) elicitneurotransmitter secretion, and hence prevent and suppress the symptomsassociated with those diseases. In addition, the compounds are expectedto have the potential to (i) increase the number of nicotiniccholinergic receptors of the brain of the patient, (ii) exhibitneuroprotective effects and (iii) when employed in effective amounts donot cause appreciable adverse side effects (e.g., significant increasesin blood pressure and heart rate, significant negative effects upon thegastro-intestinal tract, and significant effects upon skeletal muscle).The pharmaceutical compositions of the present invention are believed tobe safe and effective with regards to prevention and treatment of a widevariety of conditions and disorders.

[0011] The foregoing and other aspects of the present invention areexplained in detail in the detailed description and examples set forthbelow.

DETAILED DESCRIPTION OF THE INVENTION

[0012] The compounds of the present invention include compounds of theformula I:

[0013] where each of X and X′ are individually nitrogen, N—O or carbonbonded to a substituent species characterized as having a sigma m valuegreater than 0, often greater than 0.1, and generally greater than 0.2,and even greater than 0.3; less than 0 and generally less than −0.1; or0; as determined in accordance with Hansch et al., Chem. Rev. 91:165(1991); and m is an integer and n is an integer such that the sum of mplus n is 1, 2, 3, 4, 5, 6, 7, or 8, preferably is 1, 2, or 3, and morepreferably is 2 or 3, and most preferably 3. B′ is oxygen or sulfur, butmost preferably is oxygen. Z′ and Z″ individually represent hydrogen orlower alkyl (e.g., straight chain or branched alkyl including C₁-C₈,preferably C₁-C₅, such as methyl, ethyl, or isopropyl), Z′ and Z″individually represent hydrogen, alkyl (e.g., straight chain or branchedalkyl including C₁-C₈, preferably C₁-C₅, such as methyl, ethyl, orisopropyl), substituted alkyl, acyl, alkoxycarbonyl, or aryloxycarbonyl;and preferably at least one of Z′ and Z″ is hydrogen or both of Z′ andZ″ are hydrogen, and most preferably Z′ is hydrogen and Z″ is methyl.Alternatively, Z′ is hydrogen and Z″ represents a ring structure(cycloalkyl, heterocyclyl or aryl), such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, quinuclidinyl,pyridinyl, quinolinyl, pyrimidinyl, phenyl, benzyl, thiazolyl oroxazolyl (where any of the foregoing can be suitably substituted with atleast one substituent group, such as alkyl, alkoxyl, halo, or aminosubstituents); alternatively Z′ is hydrogen and Z″ is propargyl;alternatively Z′, Z″, and the associated nitrogen atom can form a ringstructure such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,morpholinyl, 2-imino-2,3-dihydrothiazolyl or2-imino-2,3-dihydrooxazolyl, and in certain situations, piperazinyl(e.g., piperazine); Z′ and E′″ (when n is 1) and the associated carbonand nitrogen atoms can combine to form a monocyclic ring structure suchas azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or a bicyclicring structure such as 3-(2-azabicyclo[4.2.0]octyl),3-(2-azabicyclo[2.2.2]octyl), or 3-(2-azabicyclo[2.2.1]heptyl); howeverit is preferred that when Z′ and E′″ and the associated carbon andnitrogen atoms combine to form such a ring, neither E″ nor E′ aresubstituted or unsubstituted aryl, heteroaryl, benzhydryl or benzyl; Z′,Z″ and E″ (when n is 1) and the associated carbon and nitrogen atoms cancombine to form a bicyclic ring structure such as quinuclidinyl,2-(1-azabicyclo[ 2.2.1]-heptyl), or 2-(1-azabicyclo[3.3.0]octyl), or atricyclic ring structure such as azaadamantyl; Z′, E″ and E′″ n is 1)and the associated carbon and nitrogen atoms can combine to form abicyclic ring structure such as 1-(2-azabicyclo[2.2.1]heptyl); and Z′,Z″, E″ and E′″ (when n is 1) and the associated carbon and nitrogenatoms can combine to form a tricyclic ring structure. E, E′, E″ and E′″individually represent hydrogen or a suitable non-hydrogen substituent(e.g., alkyl, substituted alkyl, halo substituted alkyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl orsubstituted arylalkyl), preferably lower alkyl (e.g., straight chain orbranched alkyl including C₁-C₈, preferably C₁-C₅, such as methyl, ethyl,or isopropyl) or halo substituted lower alkyl (e.g., straight chain orbranched alkyl including C₁-C₈, preferably C₁-C₅, such astrifluoromethyl or trichloromethyl). Generally all of E, E′, E″ and E′″are hydrogen, or at least one of E, E′, E″ and E′″ is non-hydrogen andthe remaining E, E′, E″ and E′″ are hydrogen. In addition, E and E′ orE″ and E′″ and their associated carbon atom can combine to form a ringstructure such as cyclopentyl, cyclohexyl or cycloheptyl; or E′″ and E′(when located on immediately adjacent carbon atoms) and their associatedcarbon atoms can combine to form a ring structure such as cyclopentyl,cyclohexyl or cycloheptyl. Depending upon the selection of E, E′, E″ andE′″, compounds of the present invention have chiral centers, and thepresent invention relates to racemic mixtures of such compounds as wellas enamiomeric compounds. For certain compounds, X is nitrogen; forother compounds X′ is nitrogen or N—O; and for other compounds X and X′both are nitrogen. Most preferably, X′ is nitrogen. Adjacentsubstituents of A, A′ or A″ (when X or X′ are carbon bonded to asubstituent component) can combine to form one or more saturated orunsaturated, substituted or unsubstituted carbocyclic or heterocyclicrings containing, but not limited to, ether, acetal, ketal, amine,ketone, lactone, lactam, carbamate, or urea functionalities. For certainpreferred compounds X′ is C—NR′R″, C—OR′ or C—NO₂, more preferablyC—NH₂, C—NHCH₂ or C—N(CH₃)₂, with C—NH₂ being most preferred. Inaddition, when X is carbon bonded to a substituent species, it ispreferred that the substituent species is H, Br or OR′, where R′preferably is benzyl, methyl, ethyl, isopropyl, isobutyl or tertiarybutyl. A, A′, A″ and the substituents of either X or X′ (when eachrespective X and X′ is carbon) can include H, alkyl, substituted alkyl,alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl,substituted alkylaryl, arylalkyl and substituted arylalkylfunctionalities. More specifically, X and X′ include N, N—O, C—H, C—F,C—Cl, C—Br, C—l, C—R′, C— NR′R″, C—CF₃, C—OH, C—CN, C—NO₂, C—C₂R′, C—SH,C—SCH₃, C—N₃, C—SO₂CH₃, C— OR′, C—SR′, C—C(═O)NR′R″, C—NR′C(═O)R′,C—C(═O)R′, C—C(═O)OR′, C(CH₂)_(q)OR′, C—OC(═O)R′, COC(═O)NR′R″ andC—NR′C(═O)OR′ where R′ and R″ are individually hydrogen or lower alkyl(e.g., C₁-C₁₀ alkyl, preferably C₁-C₅ alkyl, and more preferably methyl,ethyl, isopropyl or isobutyl), an aromatic group-containing species or asubstituted aromatic group-containing species, and q is an integer from1 to 6. R′ and R″ can be straight chain or branched alkyl, or R′ and R″can form a cycloalkyl funtionality (e.g., cyclopropyl cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and quinuclidinyl).Representative aromatic group-containing species include pyridinyl,quinolinyl, pyrimidinyl, phenyl, and benzyl (where any of the foregoingcan be suitably substituted with at least one substituent group, such asalkyl, halo, or amino substituents). Other representative aromatic ringsystems are set forth in Gibson et al., J. Med. Chem. 39:4065 (1996).When X and X′ represent a carbon atom bonded to a substituent species,that substituent species often has a sigma m value which is betweenabout −0.3 and about 0.75, and frequently between about −0.25 and about0.6. In certain circumstances the substituent species is characterizedas having a sigma m value not equal to 0. A, A′ and A″ individuallyrepresent those species described as substituent species to the aromaticcarbon atom previously described for X and X′; and usually includehydrogen, halo (e.g., F, Cl, Br, or I), alkyl (e.g., lower straightchain or branched C₁₋₈ alkyl, but preferably methyl or ethyl), or NX″X′″where X″ and X′″ are individually hydrogen or lower alkyl, includingC₁-C₈, preferably C₁-C₅ alkyl. In addition, it is highly preferred thatA is hydrogen, it is preferred that A′ is hydrogen, and normally A″ ishydrogen. Generally, both A and A′ are hydrogen; sometimes A and A′ arehydrogen, and A″ is amino, methyl or ethyl; and often A, A′ and A″ areall hydrogen. Depending upon the identity and positioning of eachindividual E, E, E″ and E′″, certain compounds can be optically active.Typically, the selection of E, E′, E″ and E′″ is such that up to about4, and frequently up to 3, and usually 0, 1 or 2, of the substituentsdesignated as E, E′, E″ and E′″ are non-hydrogen substituents (i.e.,substituents such as lower alkyl or halo-substituted lower alkyl).Typically, X is CH, CBr or COR. Most preferably, X′ is nitrogen.

[0014] As employed herein, “alkyl” refers to straight chain or branchedalkyl radicals including C₁-C₈, preferably C₁-C₅, such as methyl, ethyl,or isopropyl; “substituted alkyl” refers to alkyl radicals furtherbearing one or more substituent groups such as hydroxy, alkoxy,mercapto, aryl, heterocyclo, halo, amino, carboxyl, carbamyl, cyano, andthe like; “alkenyl” refers to straight chain or branched hydrocarbonradicals including C₁-C₈, preferably C₁-C₅ and having at least onecarbon-carbon double bond; “substituted alkenyl” refers to alkenylradicals further bearing one or more substituent groups as definedabove; “cycloalkyl” refers to saturated or unsaturated cyclicring-containing radicals containing three to eight carbon atoms,preferably three to six carbon atoms; “substituted cycloalkyl” refers tocycloalkyl radicals further bearing one or more substituent groups asdefined above; “aryl” refers to aromatic radicals having six to tencarbon atoms; “substituted aryl” refers to aryl radicals further bearingone or more substituent groups as defined above; “alkylaryl” refers toalkyl-substituted aryl radicals; “substituted alkylaryl” refers toalkylaryl radicals further bearing one or more substituent groups asdefined above; “arylalkyl” refers to aryl-substituted alkyl radicals;“substituted arylalkyl” refers to arylalkyl radicals further bearing oneor more substituent groups as defined above; “heterocyclyl” refers tosaturated or unsaturated cyclic radicals containing one or moreheteroatoms (e.g., O, N, S) as part of the ring structure and having twoto seven carbon atoms in the ring; “substituted heterocyclyl” refers toheterocyclyl radicals further bearing one or more substituent groups asdefined above; “acyl” refers to straight chain or branched alkyl- orsubstituted alkyl-carbonyl radicals including C₁-C₈, preferably C₁-C₅,such as formyl, acetyl, or propanoyl; “alkoxycarbonyl” refers to analkyl or substituted alkyl radical attached to an O-carbonyl moiety; and“aryloxycarbonyl” refers to an aryl or substituted aryl radical attachedto an O-carbonyl moiety.

[0015] One representative compound is (3-(3-pyridyloxy)propyl)amine, forwhich X is CH, X′ is N, B′ is O, n is 0, m is 3, and A, A′, A″, E, E′,Z′ and Z″ are each H. One representative compound is(3-(5-bromo-(3-pyridyloxy)propyl)-methylamine, for which X is C—Br, X′is N, B′ is O, n is 0, m is 3, A, A′, A″, E, E′ and Z′ are each H, andZ″ is methyl. One representative compound is(1-methyl-3-(3-pyridyloxy)propyl)methylamine, for which X is CH, X′ isN, B′ is O, n is 1, m is 2, A, A′, A″, E, E′, E″ and Z′ are each H, andE′″ and Z″ are methyl. One representative compound is(3-(5-ethoxy-(3-pyridyloxy)propyl)methylamine, for which X is C—OCH₂CH₃,X′ is N, B′ is O, n is 0, m is 3, A, A′, A″, E, E′ and Z′ are each H,and Z″ is methyl. One representative compound is(3-(6-methyl-(3-pyridyloxy)propyl)-methylamine, for which X is CH, X′ isN, B′ is O, n is 0, m is 3, A, A′, E, E′ and Z′ are each H, and A″ andZ″ each are methyl. One representative compound is(3-(5-chloro-(3-pyridyloxy)propyl) methylamine, for which X is C—Cl, X′is N, B′ is O, n is 0, m is 3, A, A′, A″, E, E′ and Z′ are each H, andZ″ is methyl. One representative compound is(3-(2-bromo(3-pyridyloxy)propyl)-methylamine, for which X is CH, X′ isN, B′ is O, n is 0, m is 3, A is Br, A′, A″, E, E′ and Z′ are each H,and Z″ is methyl. One representative compound is(1-methyl-3-(5-methoxy-(3-pyridyloxy)propyl))methylamine, for which X isC—OCH₃, X′ is N, B′ is O, n is 1, m is 2, A, A′, A″, E, E′, E″ and Z′are each H, and E′″ and Z″ are each methyl. One representative compoundis (4-(3-pyridyloxy)butyl))methylamine, for which X is CH, X′ is N, B′is O, n is 0, m is 4, A, A′, A″, E, E′, and Z′ are each H, and Z″ ismethyl. One representative example is (3-phenoxypropyl)methylamine, forwhich X and X′ are each CH, B′ is O, n is 0, m is 3, A, A′, A″, E, E′and Z′ are each H, and Z″ is methyl. One representative example is(3-(3-aminophenoxy)propyl)methylamine, for which X is CH, X′ is C—N H₂,B′ is O, n is 0, m is 3, A, A′, A″, E, E′ and Z′ are each H, and Z″ ismethyl. One representative example is(3-(4-methoxyphenoxy)propyl)-methylamine, for which X and X′ are eachCH, B′ is O, n is 0, m is 3, A, A′, E, E′ and Z′ are each H, A″ is OCH₃,and Z″ is methyl.

[0016] Exemplary other compounds that can be made in accordance with thepresent invention include (2-(5-bromo(3-pyridylthio))ethyl)methylamine,(2-(5-bromo(3-pyridylthio)) isopropyl) methylamine,(2-(5-bromo(3-pyridylthio))-propyl)methylamine and(3-(5-bromo(3-pyridylthio)) propyl)-methylamine,dimethyl(2-(3-pyridyloxy)ethylamine,dimethyl(4-(3-pyridyloxy)butyl)amine, 2-(3-pyridyloxy)ethylamine,4-(3-pyridyloxy)-butylamine,methyl(3-(5-methoxy-3-pyridyloxy)propyl)amine,ethyl(3-(3-pyridyloxy)propyl)amine, methyl(2-(3-pyridyloxy)ethyl)amine,methyl(3-(6-methyl(3-pyridyloxy))propyl)amine,(3-(3-methoxyphenoxy)propyl)-methylamine,(3-(5-chloro(3-pyridyloxy))-1-methylpropyl)methylamine,dimethyl(3-(3-pyridyloxy)propyl)amine, 3-(3-pyridyloxy)propylamine,methyl(4-(3-pyridyloxy)butyl)amine,3-(5-chloro-3-pyridyloxy)propylamine, methyl(3-(5-isopropoxy-3-pyridyloxy)propyl)amine, (3-(5-chloro(3-pyridyloxy))propyl) methylamine,methyl(3-(5-(phenyl methoxy) (3-pyridyloxy))propyl)amine,methyl(3-(2-methyl(3-pyridyloxy))propyl)amine,(methylethyl)(3-(3-pyridyloxy)propyl)amine,benzyl (3-(3-pyridyloxy)propyl)-amine,cyclopropyl(3-(3-pyridyloxy)propyl)amine,methyl(1-methyl-3-(3-pyridyloxy)propyl)amine,methyl(3-(3-nitrophenoxy)propyl)amine,1-(3-chloropropoxy)-3-nitrobenzene,(3-(3-aminophenoxy)propyl)methylamine,dimethyl(3-(3-(methylamino)propoxy)phenyl)amine, methyl(3-tricyclo[7.3.1.0<5,13>]tridec-2-yloxypropyl)amine, (3-benzo[3,4-d]1,3-dioxolan-5-yloxypropyl)methylamine, 3-(4-piperidinyloxy)pyridine,3-((3S)-3-pyrrolidinyloxy)pyridine,methyl(3-(5-(3,4-dimethoxybenzyloxy)(3-pyridyloxy))propyl)methylamine,methyl(3-(3-quinolyloxy)propyl)amine,3-(5-bromo-3-pyridylthio))propyl)methylamine and3-((3S)-(1-methyl-3-pyrrolidinyloxy)pyridin.

[0017] The manner in which certain phenoxyalkylamine compounds of thepresent invention are provided can vary. Certain phenoxyalkylaminecompounds can be prepared by the alkylation of phenol with a1,3-dihalopropane, such as 1,3-dichloropropane, 1,3-dibromopropane,1,3-diiodopropane, or 1-chloro-3-iodopropane, which are commerciallyavailable from Aldrich Chemical Company, in the presence of a base(e.g., sodium hydride) in dry N,N-dimethylformamide. The resulting3-halo-1-phenoxypropane can be converted to a phenoxyalkylamine, such asmethyl(3-phenoxypropyl)amine, by treatment with methylamine in asolvent, such as tetrahydrofuran or aqueous methanol. The manner inwhich certain 3-substituted-phenyl analogs of(3-phenoxypropyl)methylamine of the present invention can besynthetically prepared is analogous to that described for thepreparation of methyl(3-phenoxypropyl)amine with the exception that3-substituted-phenols are employed rather than phenol. In someinstances, protecting groups may be employed when necessary. Forexample, one representative compound,(3-(3-aminophenoxy)propyl)methylamine can be prepared by the alkylationof an N-phthalamido-protected phenol,2-(3-hydroxyphenyl)isoindoline-1,3-dione (prepared by treatment of3-aminophenol with phthalic anhydride) with 1-chloro-3-iodopropane. Theresulting intermediate,2-(3-(3-chloropropoxy)-phenyl)isoindoline-1,3-dione can be converted to(3-(3-aminophenoxy)-propyl)methylamine by treatment with methanolicmethylamine. The manner in which certain 4-substituted-phenyl analogs ofmethyl(3-phenoxypropyl)amine of the present invention can besynthetically prepared is analogous to that described for thepreparation of methyl(3-phenoxypropyl)amine with the exception that4-substituted-phenols are employed rather than phenol. For example,4-methoxyphenol can be converted to(3-(4-methoxyphenoxy)propyl)-methylamine.

[0018] The manner by which pyridyloxyalkylamine compounds of the presentinvention are provided can vary. Certain pyridyloxyalkylamine compoundscan be prepared by the alkylation of 3-hydroxypyridine with a1,3-dihalopropane, such as 1,3-dichloropropane, 1,3-dibromopropane,1,3-diodopropane or 1-chloro-3-iodopropane, which are commerciallyavailable from Aldrich Chemical Company, in the presence of a base(e.g., sodium hydride) in dry N,N-dimethylformamide. The resulting3-halo-1-(3-pyridyloxy)propane can be converted to apyridyloxyalkylamine, such as (3-(3-pyridyloxy)propyl)-methylamine, bytreatment with methylamine in a solvent, such as tetrahydrofuran oraqueous methanol. One representative compound,(3-(3-pyridyloxy)propyl)methylamine is prepared by the reaction of3-hydroxypyridine with 1.2 molar equivalents of 1-chloro-3-iodopropaneand 1.6 molar equivalents of sodium hydride in dry N,N-dimethylformamideat ambient temperature. The resulting intermediate,3-chloro-1-(3-pyridyloxy)propane, obtained in about 54% yield, isconverted to (3-(3-pyridyloxy)propyl)methylamine in about 40% yield, bytreatment with an excess (25 molar equivalents) of aqueous methylaminein methanol, assisted by heating. Certain pyridyloxyalkylaminecompounds, such as (4-(3-pyridyloxy)-butyl)methylamine, can be preparedby alkylating 3-hydoxypyridine with a 1,4-dihalobutane, such as1,4-diiodobutane, 1,4-dibromobutane, 1,4-dichlorobutane or1-chloro-4-iodobutane, which are commercially available from AldrichChemical Company, in the presence of a base (e.g., sodium hydride) inN,N-dimethylformamide. The resulting 4-halo-1-(3-pyridyloxy)butane canbe converted to a pyridyloxyalkylamine, such as(4-(3-pyridyloxy)butyl)methylamine, by treatment with methylamine in asolvent, such as tetrahydrofuran or aqueous methanol.

[0019] The manner by which certain 2-substituted-3-pyridyl analogs of(3-(3-pyridyloxy)propyl)methylamine and certain 6-substituted-3-pyridylanalogs of (3-(3-pyridyloxy)propyl)methylamine of the present inventioncan be synthetically prepared is analogous to that described for thepreparation of (3-(3-pyridyloxy)-propyl)methylamine with the exceptionthat 2-substituted-3-hydroxypyridines and6-substituted-3-hydroxypyridines are employed rather than3-hydroxypyridine. For example, using such methodology, commerciallyavailable 2-bromo-3-hydroxypyridine and 3-hydroxy-2-nitropyridine can beconverted to 3-(2-bromo(3-pyridyloxy))propyl)-methylamine and3-(2-nitro(3-pyridyloxy))-propyl)methylamine, respectively. Similarly,commercially available 3-hydroxy-6-methylpyridine can be converted to3-(6-methyl(3-pyridyloxy))propyl)-methylamine.

[0020] The manner by which certain 5-substituted-3-pyridyl analogs of(3-(3-pyridyloxy)propyl)methylamine of the present invention can besynthesized is analogous to that described for(3-(3-pyridyloxy)propyl)methylamine, with the exception that5-substituted-3-hydroxypyridines are employed rather than3-hydroxypyridine. For example, using such a methodology,5-bromo-3-hydroxypyridine can be converted to the intermediate,3-chloro-1-(5-bromo-3-pyridyloxy)propane, which is converted to3-(5-bromo(3-pyridyloxy))-propyl)methylamine. 5-Bromo-3-hydroxypyridinecan be prepared form 2-furfurylamine using the procedure described inU.S. Pat. No. 4,192,946 to Clauson-Kaas et al. the disclosure of whichis incorporated herein by reference in its entirety. In a similarmanner, 5-chloro-3-hydroxypyridine, which is commercially available fromAldrich Chemical Company, can be converted to3-(5-chloro(3-pyridyloxy))propyl)methylamine. Similarly,5-methoxy-3-hydroxypyridine, prepared according to the procedures setforth in Chen et al., Heterocycles 24(12): 3411 (1986), can be convertedto 3-(5-methoxy(3-pyridyloxy))propyl)methylamine. Similarly,5-ethoxy-3-hydroxypyridine can be converted to3-(5-ethoxy(3-pyridyloxy))propyl)-methylamine. Similarly,5-amino-3-hydroxypyridine, prepared according to the procedures setforth in Tamura et al., Heterocycles 15(2): 871 (1981), can be convertedto 3-(5-amino(3-pyridyloxy))propyl)methylamine. In a similar manner,3-hydroxy-5-trifluoromethylpyridine and2-fluoro-5-hydroxy-3-methylpyridine, each prepared using methods setforth in PCT WO 96/40682, can be converted to 3-(5-trifluoromethyl(3-pyridyloxy))propyl)methyl amine and3-(6-fluoro-5-methyl(3-pyridyloxy))propyl)methylamine, respectively.

[0021] A number of 5-substituted analogs, such as(3-(5-substituted(3-pyridyloxy))propyl)methylamine, can be synthesizedfrom 5-substituted 3-hydroxypyridines, which can be prepared from5-amino-3-hydroxypyridine via a diazonium salt intermediate. Forexample, 5-amino-3-hydroxypyridine can be converted to5-fluoro-3-hydroxypyridine, 5-chloro-3-hydroxypyridine,5-bromo-3-hydroxypyridine, 5-iodo-3-hydroxypyridine or5-cyano-3-hydroxypyridine, using the general techniques set forth inZwart et al., Recueil Trav. Chim. Pays-Bas 74: 1062 (1955). Furthermore,5-hydroxy-substituted analogs can be prepared from the reaction of thecorresponding 5-diazonium salt intermediate with water. The5-Fluoro-substituted analogs can be prepared from the reaction of the5-diazonium salt intermediate with fluoroboric acid.5-Chloro-substituted analogs can be prepared from the reaction of5-amino-3-hydroxypyridine with sodium nitrite and hydrochloric acid inthe presence of copper chloride. The 5-cyano-substituted analogs can beprepared from the reaction of the corresponding diazonium saltintermediate with potassium copper cyanide. The 5-amino-substitutedanalogs can be converted to the corresponding 5-nitro analogs byreaction with fuming sulfuric acid and peroxide according to the generaltechniques described in Morisawa, J. Med. Chem. 20: 129 (1977), forconverting an amino pyridine to a nitropyridine.

[0022] Certain pyridyloxyalklylamines that possess a branched sidechain, such as (1-methyl-3-(3-pyridyloxy)propyl)methylamine, can beprepared by alkylating 3-hydroxypyridine with a protected3-hydroxy-1-halobutane, such as3-[(tert-butyl)dimethylsilyloxy]-1-bromobutane (prepared according tothe procedures set forth in Gerlach et al., Helv. Chim. Acta. 60(8):2860 (1977)), thereby producing a (tert-butyl)dimethylsilyl protected4-(3-pyridyloxy)butan-2-ol. The (tert-butyl)dimethylsilyl group can beremoved by treatment with ammonium fluoride or aqueous acetic acid togive 4-(3-pyridyloxy)butan-2-ol. Mesylation or tosylation of thatcompound with methanesulfonyl chloride in triethylamine orp-toluenesulfonyl chloride in pyridine, followed by treatment withmethylamine in tetrahydrofuran or aqueous methanol, provides a compoundhaving a methyl branched side chain (e.g.,(1-methyl-3-(3-pyridyloxy)propyl)methylamine).

[0023] Alternatively, pyridyloxyalkylamines possessing a branched sidechain, such as (1-methyl-3-(3-pyridyloxy)propyl)methylamine, can besynthesized by alkylating 3-hydroxypyridine with a protected1-iodo-3-butanone, namely 2-methyl-2-(2-iodoethyl)-1,3-dioxolane, withis prepared according to the procedures set forth in Stowell et al., J.Org. Chem. 48: 5381 (1983). The resulting ketal,3-(2-(1-methyl-2,5-dioxolanyl)ethoxy)pyridine, can be protected bytreatment with aqueous acetic acid or p-toluenesulfonic acid in methanolto yield 4-(3-pyridyloxy)butan-2-one. Reductive amination of theresulting ketone using methylamine and sodium cyanoborohydride accordingto the methodology set forth in Borch, Org. Syn. 52: 124 (1972) provides(1-methyl-3-(3-pyridyloxy)propyl)methylamine. Alternatively, theintermediate, 4-(3-pyridyloxy)butan-2-one, can be reduced with sodiumborohydride to yield an alcohol, 4-(3-pyridyloxy)butan-2-ol. Mesylationor tosylation of that alcohol, followed by mesylation or tosylationdisplacement using methylamine, provides the branched chainpyridyloxyalkylamine, (1-methyl-3-(3-pyridyloxy)propyl)-methylamine.

[0024] Chiral starting materials are available for the synthesis of thepure enantiomers of the branched chain pyridyloxyalkylamines, such a(1-methyl-3-(3-pyridyloxy)proyl)methylamine. One approach can be carriedout using either methyl(R)-(−)-3-hydroxybutyrate or the (+)-enantiomer,(S)-(+)-3-hydroxybutyrate, both of which are available from AldrichChemical Company. For example, (R)-(−)-3-hydroxybutyrate can beconverted to (R)-(−)-3-tetrahydropyranyloxybutyl bromide, using theprocedures set forth in Yuasa et al., J. Chem. Soc., Perk. Trans. 1(5):465 (1996). Alkylation of 3-hyroxypyridine with(R)-(−)-3-tetrahydropyranyloxybutyl bromide using sodium hydride inN,N-dimethylformamide produces the tetrahydropyranyl ether of4-(3-pyridyloxy)butan-2R-ol. Removal of the tetrahydropyranyl protectinggroup of that compound using p-toluenesulfonic acid monohydrate inmethanol affords 4-(3-pyridyloxy)butan-2R-ol. The resulting chiralalcohol can be elaborated to the chiral pyridyloxyalkylamine,(1S-3-(3-pyridyloxy)propyl)-methylamine using a two-step sequenceinvolving tosylation and methylamine displacement of the intermediatetosylate. In a similar process, (S)-(+)-3-hydroxybutyrate can beconverted to (S)-(+)-3-tetrahydropyranyloxybutyl bromide using theprocedures set forth in Sakai et al., Agric. Biol. Chem. 50(6): 1621(1986). This protected bromo alcohol can be converted to thecorresponding chiral pyridyloxyalkylamine,methyl(1R-3-(3-pyridyloxy)-propyl)amine, using a sequence involvingalkylation of 3-hydroxypyridine, removal of the tetrahydropyranyl group,tosylation, and methylamine displacement of the intermediate tosylate.

[0025] The manner by which certain 5-alkoxy-3-pyridyl analogs ofmethyl(3-(3-pyridyloxy)propyl)amine of the present invention can besynthesized is analogous to that described for the synthesis ofmethyl(3-(3-pyridyloxy)-propyl)amine with the exception that5-alkoxy-3-hydroxypyridines are employed rather than 3-hydroxypyridine.For example, 3,5-dibromopyridine (commercially available from AldrichChemical Company and Lancaster Synthesis Inc.) can be converted to thesynthetic intermediate, 5-(3,4-dimethoxybenzyloxy)-3-bromopyridine byheating at 100° C. with veratryl alcohol (3,4-dimethoxybenzyl alcohol)in the presence of sodium and copper powder. The resulting5-(3,4-dimethoxybenzyloxy)-3-bromopyridine can be heated at 180° C. withconcentrated aqueous ammonia in the presence of copper(II) sulfate orcopper (I) bromide to produce the aminopyridine compound,5-(3,4-dimethoxybenzyloxy)-3-aminopyridine. The latter compound can bediazotized and the diazonium salt hydrolyzed by treatment with sodiumnitrite and aqueous sulfuric acid to give the hydroxypyridine,5-(3,4-dimethoxybenzyloxy)-3-hydroxypyridine. This5-substituted-3-hydroxypyridine can be alkylated with1-chloro-3-iodopyridine in the presence of sodium hydride inN,N-dimethylformamide to yield3-chloro-1-(5-(3,4-dimethoxybenzyloxy)-3-pyridyloxy)propane. Treatmentof the latter compound with an excess of methylamine in methanol willaffordmethyl(3-(5-(3,4-dimethoxybenzyloxy)(3-pyridyloxy))propyl)methylamine.

[0026] Certain commercially available fused polycyclic haloaromatics canbe used as starting materials to prepare compounds of the presentinvention which possess fused rings. For example, 3-bromoquinoline(commercially available from Aldrich Chemical Company) can be convertedto 3-aminoquinoline by heating at ˜180° C. with aqueous ammonia in thepresence of copper(II) sulfate or copper(l) bromide. The resulting3-aminoquinoline (commercially available from Aldrich Chemical Company)can be diazotized and subsequently hydrolyzed by treatment with sodiumnitrite and aqueous sulfuric acid to produce 3-hydroxyquinolineaccording to the methodology of C. Naumann and H. Langhals, Synthesis(4): 279-281 (1990). 3-Hydroxyquinoline can be alkylated with1-chloro-3-iodopyridine in the presence of sodium hydride andN,N-dimethylformamide to give 3-chloro-1-(3-quinolyloxy)propane.Treatment of the latter compound with aqueous methylamine will givemethyl(3-(3-quinolyloxy)propyl)amine.

[0027] Compounds of the present invention possessing a thioether moietycan be prepared from an appropriately substituted pyridine such as3,5-dibromopyridine (commercially available from Aldrich ChemicalCompany and Lancaster Synthesis Inc.). As an example,3,5-dibromopyridine can be treated with 3-mercapto-1-propanol in thepresence of sodium hydroxide and N,N-dimethylformamide to give3-(5-bromo-3-pyridylthio)propan-1-ol. Treatment of the latter compoundwith p-toluenesulfonyl chloride, followed by treatment of theintermediate tosylate with aqueous methylamine will afford3-(5-bromo-3-pyridylthio))propyl)methylamine.

[0028] Compounds of the present invention that are ethers and possess acyclic amine functionality can be prepared from hydroxypyridines andhydroxylated cyclic amines using the general coupling method of O.Mitsunobu, Synthesis: 1 (1981). For example,3-((3S)-(1-methyl-3-pyrrolidinyloxy)pyridine can be synthesized by thecoupling of 3-hydroxypyridine and(3R)-N-(tert-butoxycarbonyl)-3-hydroxypyrrolidine in the presence oftriphenylphosphine and diethyl azodicarboxylate in tetrahydrofuran. Theresulting intermediate,3-((3S)-N-(tert-butoxycarbonyl)-3-pyrrolidinyloxy)pyridine can then betreated with a strong acid such as trifluoroacetic acid to remove thetert-butoxycarbonyl protecting group to produce3-((3S)-3-pyrrolidinyloxy)pyridine. The latter compound can beN-methylated to afford 3-((3S)-(1-methyl-3-pyrrolidinyloxy)pyridine.Methylation methods employing aqueous formaldehyde and sodiumcyanoborohydride as described by M. A. Abreo et al., J. Med. Chem. 39:817-825 (1996) can be used. The N-protected starting material, (3R)-N-(tert-butoxycarbonyl)-3-hydroxypyrrolidine can be prepared from(R)-(+)-3-pyrrolidinol (commercially available from Aldrich ChemicalCompany) according to the general techniques described by P. G. Houghtonet al.,J. Chem. Soc. Perkin Trans 1 (Issue 13): 1421-1424 (1993). Such acompound is exemplary of a compound whereby E and Z′ combine to form aring; and in a similar manner, if m=0, Z′ and E′″ can combine to form aring.

[0029] The present invention relates to a method for providingprevention of a condition or disorder to a subject susceptible to such acondition or disorder, and for providing treatment to a subjectsuffering therefrom. For example, the method comprises administering toa patient an amount of a compound effective for providing some degree ofprevention of the progression of a CNS disorder (i.e., provideprotective effects), amelioration of the symptoms of a CNS disorder, andamelioration of the reoccurrence of a CNS disorder. The method involvesadministering an effective amount of a compound selected from thegeneral formulae which are set forth hereinbefore. The present inventionrelates to a pharmaceutical composition incorporating a compoundselected from the general formulae which are set forth hereinbefore. Thepresent invention also relates to prodrug derivatives of the compoundsof the present invention. The compounds normally are not opticallyactive. However, certain compounds can possess substituent groups of acharacter so that those compounds possess optical activity. Opticallyactive compounds can be employed as racemic mixtures or as enantiomers.The compounds can be employed in a free base form or in a salt form(e.g., as pharmaceutically acceptable salts). Examples of suitablepharmaceutically acceptable salts include inorganic acid addition saltssuch as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate;organic acid addition salts such as acetate, galactarate, propionate,succinate, lactate, glycolate, malate, tartrate, citrate, maleate,fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; saltswith acidic amino acid such as aspartate and glutamate; alkali metalsalts such as sodium salt and potassium salt; alkaline earth metal saltssuch as magnesium salt and calcium salt; ammonium salt; organic basicsalts such as trimethylamine salt, triethylamine salt, pyridine salt,picoline salt, dicyclohexylamine salt, and N,N′-dibenzylethylenediaminesalt; and salts with basic amino acid such as lysine salt and argininesalt. The salts may be in some cases hydrates or ethanol solvates.

[0030] Compounds of the present invention are useful for treating thosetypes of conditions and disorders for which other types of nicotiniccompounds have been proposed as therapeutics. See, for example, Williamset al. DN&P 7(4):205-227 (1994), Arneric et al., CNS Drug Rev. 1(1):1-26(1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1):79-100 (1996),Bencherif et al., JPET 279:1413 (1996), Lippiello et al., JPET279:1422(1996), Damaj et al., Neuroscience (1997), Holladay et al., J. Med. Chem40(28): 41694194 (1997), Bannon et al., Science 279: 77-80 (1998), PCTWO 94/08992, PCT WO 96/31475, and U.S. Pat. Nos. 5,583,140 to Bencherifet al., 5,597,919 to Dull et al., and 5,604,231 to Smith et al thedisclosures of which are incorporated herein by reference in theirentirety. Compounds of the present invention can be used as analgesics,to treat ulcerative colitis, to treat a variety of neurodegenerativediseases, and to treat convulsions such as those that are symtematic ofepilepsy. CNS disorders which can be treated in accordance with thepresent invention include presenile dementia (early onset Alzheimer'sdisease), senile dementia (dementia of the Alzheimer's type),HIV-dementia, multiple cerebral infarcts, Parkinsonism includingParkinson's disease, Pick's disease, Huntington's chorea, tardivedyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety,depression, mild cognitive impairment, dyslexia, schizophrenia andTourette's syndrome. Compounds of the present invention also can be usedto treat conditions such as syphillis and Creutzfeld-Jakob disease.

[0031] The pharmaceutical composition also can include various othercomponents as additives or adjuncts. Exemplary pharmaceuticallyacceptable components or adjuncts which are employed in relevantcircumstances include antioxidants, free radical scavenging agents,peptides, growth factors, antibiotics, bacteriostatic agents,immunosuppressives, anticoagulants, buffering agents, anti-inflammatoryagents, anti-pyretics, time release binders, anaesthetics, steroids andcorticosteroids. Such components can provide additional therapeuticbenefit, act to affect the therapeutic action of the pharmaceuticalcomposition, or act towards preventing any potential side effects whichmay be posed as a result of administration of the pharmaceuticalcomposition. In certain circumstances, a compound of the presentinvention can be employed as part of a pharmaceutical composition withother compounds intended to prevent or treat a particular disorder.

[0032] The manner in which the compounds are administered can vary. Thecompounds can be administered by inhalation (e.g., in the form of anaerosol either nasally or using delivery articles of the type set forthin U.S. Pat. No. 4,922,901 to Brooks et al., the disclosure of which isincorporated herein in its entirety); topically (e.g., in lotion form);orally (e.g., in liquid form within a solvent such as an aqueous ornon-aqueous liquid, or within a solid carrier); intravenously (e.g.,within a dextrose or saline solution); as an infusion or injection(e.g., as a suspension or as an emulsion in a pharmaceuticallyacceptable liquid or mixture of liquids); intrathecally; intracerebroventricularly; or transdermally (e.g., using a transdermal patch).Although it is possible to administer the compounds in the form of abulk active chemical, it is preferred to present each compound in theform of a pharmaceutical composition or formulation for efficient andeffective administration. Exemplary methods for administering suchcompounds will be apparent to the skilled artisan. For example, thecompounds can be administered in the form of a tablet, a hard gelatincapsule or as a time release capsule. As another example, the compoundscan be delivered transdermally using the types of patch technologiesavailable, for example, from Novartis and Alza Corporation. Theadministration of the pharmaceutical compositions of the presentinvention can be intermittent, or at a gradual, continuous, constant orcontrolled rate to a warm-blooded animal, (e.g., a mammal such as amouse, rat, cat, rabbit, dog, pig, cow, or monkey); but advantageouslyis preferably administered to a human being. In addition, the time ofday and the number of times per day that the pharmaceutical formulationis administered can vary. Administration preferably is such that theactive ingredients of the pharmaceutical formulation interact withreceptor sites within the body of the subject that effect thefunctioning of the CNS. More specifically, in treating a CNS disorderadministration preferably is such so as to optimize the effect uponthose relevant receptor subtypes which have an effect upon thefunctioning of the CNS, while minimizing the effects upon muscle-typereceptor subtypes. Other suitable methods for administering thecompounds of the present invention are described in U.S. Pat. No.5,604,231 to Smith et al.

[0033] The appropriate dose of the compound is that amount effective toprevent occurrence of the symptoms of the disorder or to treat somesymptoms of the disorder from which the patient suffers. By “effectiveamount”, “therapeutic amount” or “effective dose” is meant that amountsufficient to elicit the desired pharmacological or therapeutic effects,thus resulting in effective prevention or treatment of the disorder.Thus, when treating a CNS disorder, an effective amount of compound isan amount sufficient to pass across the blood-brain barrier of thesubject, to bind to relevant receptor sites in the brain of the subject,and to activatie relevant nicotinic receptor subtypes (e.g., provideneurotransmitter secretion, thus resulting in effective prevention ortreatment of the disorder). Prevention of the disorder is manifested bydelaying the onset of the symptoms of the disorder. Treatment of thedisorder is manifested by a decrease in the symptoms associated with thedisorder or an amelioration of the reoccurrence of the symptoms of thedisorder.

[0034] The effective dose can vary, depending upon factors such as thecondition of the patient, the severity of the symptoms of the disorder,and the manner in which the pharmaceutical composition is administered.For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount sufficient to activaterelevant receptors to effect neurotransmitter (e.g., dopamine) releasebut the amount should be insufficient to induce effects on skeletalmuscles and ganglia to any significant degree. The effective dose ofcompounds will of course differ from patient to patient but in generalincludes amounts starting where CNS effects or other desired therapeuticeffects occur, but below the amount where muscular effects are observed.

[0035] Typically, the effective dose of compounds generally requiresadministering the compound in an amount of less than 1 ug/kg of patientweight. Often, the compounds of the present invention are administeredin an amount from 10 ng to less than 1 ug/kg of patient weight,frequently between about 0.1 ug to less than 1 ug/kg of patient weight,and preferably between about 0.1 ug to about 0.5 ug/kg of patientweight. Compounds of the present invention can be administered in anamount of 0.3 to 0.5 ug/kg of patient weight. For compounds of thepresent invention that do not induce effects on muscle type nicotinicreceptors at low concentrations, the effective dose is less than 50ug/kg of patient weight; and often such compounds are administered in anamount from 0.5 ug to less than 50 ug/kg of patient weight. Theforegoing effective doses typically represent that amount administeredas a single dose, or as one or more doses administered over a 24 hourperiod.

[0036] For human patients, the effective dose of typical compoundsgenerally requires administering the compound in an amount of at leastabout 1, often at least about 10, and frequently at least about 25 ug/24hr./patient. For human patients, the effective dose of typical compoundsrequires administering the compound which generally does not exceedabout 500, often does not exceed about 400, and frequently does notexceed about 300 ug/24 hr./patient. In addition, administration of theeffective dose is such that the concentration of the compound within theplasma of the patient normally does not exceed 500 ng/ml, and frequentlydoes not exceed 100 ng/ml.

[0037] The compounds useful according to the method of the presentinvention have the ability to pass across the blood-brain barrier of thepatient. As such, such compounds have the ability to enter the centralnervous system of the patient. The log P values of typical compounds,which are useful in carrying out the present invention are generallygreater than about −0.5, often are greater than about 0, and frequentlyare greater than about 0.5. The log P values of such typical compoundsgenerally are less than about 3, often are less than about 2, andfrequently are less than about 1. Log P values provide a measure of theability of a compound to pass across a diffusion barrier, such as abiological membrane. See, Hansch, et al., J. Med. Chem. 11:1 (1968).

[0038] The compounds useful according to the method of the presentinvention have the ability to bind to, and in most circumstances, causeactivation of, nicotinic dopaminergic receptors of the brain of thepatient. As such, such compounds have the ability to express nicotinicpharmacology, and in particular, to act as nicotinic agonists. Thereceptor binding constants of typical compounds useful in carrying outthe present invention generally exceed about 0.1 nM, often exceed about1 nM, and frequently exceed about 10 nM. The receptor binding constantsof certain compounds are less than about 100 uM, often are less thanabout 10 uM and frequently are less than about 5 uM; and of preferredcompounds generally are less than about 1 uM, often are less than about100 nM, and frequently are less than about 50 nM. Though not preferred,certain compounds possess receptor binding constants of less than 10 uM,and even less than 100 uM. Receptor binding constants provide a measureof the ability of the compound to bind to half of the relevant receptorsites of certain brain cells of the patient. See, Cheng, et al.,Biochem. Pharmacol. 22:3099 (1973).

[0039] The compounds useful according to the method of the presentinvention have the ability to demonstrate a nicotinic function byeffectively activating neurotransmitter secretion from nerve endingpreparations (i.e., synaptosomes). As such, such compounds have theability to activate relevant neurons to release or secreteacetylcholine, dopamine, and other neurotransmitters. Generally, typicalcompounds useful in carrying out the present invention provide for theactivation of dopamine secretion in amounts of at least one third,typically at least about 10 times less, frequently at least about 100times less, and sometimes at least about 1,000 times less, than thoserequired for activation of muscle-type nicotinic receptors. Certaincompounds of the present invention can provide secretion of dopamine inan amount which is comparable to that elicited by an equal molar amountof (S)-(−)-nicotine.

[0040] The compounds of the present invention, when employed ineffective amounts in accordance with the method of the presentinvention, are selective to certain relevant nicotinic receptors, but donot cause significant activation of receptors associated withundesirable side effects at concentrations at least greater than thoserequired for activation of dopamine release. By this is meant that aparticular dose of compound resulting in prevention and/or treatment ofa CNS disorder, is essentially ineffective in eliciting activation ofcertain muscle-type nicotinic receptors at concentration higher than 5times, preferably higher than 100 times, and more preferably higher than1,000 times, than those required for activation of dopamine release.This selectivity of certain compounds of the present invention againstthose ganglia-type receptors responsible for cardiovascular side effectsis demonstrated by a lack of the ability of those compounds to activatenicotinic function of adrenal chromaffin tissue at concentrationsgreater than those required for activation of dopamine release.

[0041] Compounds of the present invention, when employed in effectiveamounts in accordance with the method of the present invention, areeffective towards providing some degree of prevention of the progressionof CNS disorders, amelioration of the symptoms of CNS disorders, anamelioration to some degree of the reoccurrence of CNS disorders.However, such effective amounts of those compounds are not sufficient toelicit any appreciable side effects, as demonstrated by increasedeffects relating to skeletal muscle. As such, administration of certaincompounds of the present invention provides a therapeutic window inwhich treatment of certain CNS disorders is provided, and certain sideeffects are avoided. That is, an effective dose of a compound of thepresent invention is sufficient to provide the desired effects upon theCNS, but is insufficient (i.e., is not at a high enough level) toprovide undesirable side effects. Preferably, effective administrationof a compound of the present invention resulting in treatment of CNSdisorders occurs upon administration of less than ⅕, and often less than{fraction (1/10)} that amount sufficient to cause certain side effectsto any significant degree.

[0042] The pharmaceutical compositions of the present invention can beemployed to prevent or treat certain other conditions, diseases anddisorders. Exemplary of such diseases and disorders include inflammatorybowel disease, acute cholangitis, aphteous stomatitis, arthritis (e.g.,rheumatoid arthritis and ostearthritis), neurodegenerative diseases,cachexia secondary to infection (e.g., as occurs in AIDS, AIDS relatedcomplex and neoplasia), as well as those indications set forth in PCT WO98/25619. The pharmaceutical compositions of the present invention canbe employed in order to ameliorate may of the symptoms associated withthose conditions, diseases and disorders. Thus, pharmaceuticalcompositions of the present invention can be used in treating geneticdiseases and disorders, in treating autoimmune disorders such as lupus,as anti-infectious agents (e.g, for treating bacterial, fungal and viralinfections, as well as the effects of other types of toxins such assepsis), as anti-inflammatory agents (e.g., for treating acutecholangitis, aphteous stomatitis, asthma, and ulcerative colitis), andas inhibitors of cytokines release (e.g., as is desirable in thetreatment of cachexia, inflammation, neurodegenerative diseases, viralinfection, and neoplasia), The compounds of the present invention canalso be used as adjunct therapy in combination with existing therapiesin the management of the aforementioned types of diseases and disorders.In such situations, administration preferably is such that the activeingredients of the pharmaceutical formulation act to optimize effectsupon abnormal cytokine production, while minimizing effects uponreceptor subtypes such as those that are associated with muscle andganglia. Administration preferably is such that active ingredientsinteract with regions where cytokine production is affected or occurs.For the treatment of such conditions or disorders, compounds of thepresent invention are very potent (i.e., affect cytokine productionand/or secretion at very low concentrations), and are very efficacious(i.e., significantly inhibit cytokine production and/or secretion to arelatively high degree). Effective doses are most preferably at very lowconcentrations, where maximal effects are observed to occur.Concentrations, determined as the amount of compound per volume ofrelevant tissue, typically provide a measure of the degree to which thatcompound affects cytokine production. For human patients, the effectivedose of typical compounds generally requires administering the compoundin an amount of at least about 1, often at least about 10, andfrequently at least about 25 ug/24 hr./patient. For human patients, theeffective dose of typical compounds requires administering the compoundwhich generally does not exceed about 1, often does not exceed about0.75, often does not exceed about 0.5, frequently does not exceed about0.25 mg/24 hr./patient. In addition, administration of the effectivedose is such that the concentration of the compound within the plasma ofthe patient normally does not exceed 500 pg/ml, often does not exceed300 pg/ml, and frequently does not exceed 100 pg/ml. When employed insuch a manner, compounds of the present invention are dose dependent,and as such, cause inhibition of cytokine production and/or secretionwhen employed at low concentrations but do not exhibit those inhibitingeffects at higher concentrations. Compounds of the present inventionexhibit inhibitory effects upon cytokine production and/or secretionwhen employed in amounts less than those amounts necessary to elicitactivation of relevant nicotinic receptor subtypes to any significantdegree.

[0043] The following examples are provided to illustrate the presentinvention, and should not be construed as limiting thereof. In theseexamples, all parts and percentages are by weight, unless otherwisenoted.

EXAMPLES Example 1

[0044] Determination of Binding to Relevant Receptor Sites

[0045] Binding of the compounds to relevant receptor sites wasdetermined in accordance with the techniques described in U.S. Pat. No.5,597,919 to Dull et al. Inhibition constants (Ki values), reported innM, were calculated from the IC₅₀ values using the method of Cheng etal., Biochem, Pharmacol. 22:3099 (1973). Low binding constants indicatethat the compounds of the present invention exhibit good high affinitybinding to certain CNS nicotinic receptors.

Example 2

[0046] Neurotransmitter Release From Brain Synaptosomes

[0047] Neurotransmitter release was measured using techniques similar tothose previously published (Bencherif M, et al.:. JPET 279: 1413-1421,1996).

[0048] Rat brain synaptosomes were prepared as follows: Female SpragueDawley rats (100-200 g) were killed by decapitation after anesthesiawith 70% CO₂. Brains are dissected, and hippocampus, striatum, andthalamus isolated, and homogenized in 0.32 M sucrose containing 5 mMHEPES pH 7.4 using a glass/glass homogenizer. The tissue was thencentrifuged for 1000×g for 10 minutes and the pellet discarded. Thesupernatant was centrifuged at 12000×g for 20 minutes. The resultantpellet was re-suspended in perfusion buffer (128 mM NaCl, 1.2 mM KH₂PO₄,2.4 mM KCl, 3.2 mM CaCl₂, 1.2 mM MgSO₄, 25 mM HEPES, 1 mM Ascorbic acid,0.01 mM pargyline HCl and 10 mM glucose pH 7.4) and centrifuged for 15minutes at 25000×g. The final pellet was resuspended in perfusion bufferand placed in a water bath (37° C.) for 10 minutes. Radiolabeledneurotransmitter is added (30 L³H DA, 20 L³H NE, 10 L³H glutamate) toachieve a final concentration of 100 nM, vortexed and placed in a waterbath for additional 10 minutes. Tissue-loaded filters is placed onto11-mm diameter Gelman A/E filters on an open-air support. After a10-minute wash period, fractions are collected to establish the basalrelease and agonist applied in the perfusion stream. Further fractionswere collected after agonist application to re-establish the baseline.The perfusate was collected directly into scintillation vials andreleased radioactivity was quantified using conventional liquidscintillation techniques. Release of neurotransmitter was determined inthe presence of 10 M of various ligands and was expressedas a percentageof release obtained with a concentration of 10 M (S)-(−)-nicotine or 300MTMA resulting in maximal effects.

Example 3

[0049] Determination of Interaction with Muscle Receptors

[0050] The determination of the interaction of the compounds with musclereceptors was carried out in accordance with the techniques described inU.S. Pat. No. 5,597,919 to Dull et al. The maximal activation forindividual compounds (E_(max)) was determined as a percentage of themaximal activation induced by (S)-(−)-nicotine. Reported E_(max) valuesrepresent the amount released relative to (S)-(−)-nicotine on apercentage basis. Low E_(max) values at muscle-type receptors indicatethat the compounds of the present invention do not induce activation ofmuscle-type receptors. Such preferable compounds have the capability toactivate human CNS receptors without activating muscle-type nicotinicacetylcholine receptors. Thus, there is provided a therapeutic windowfor utilization in the treatment of CNS disorders. That is, at certainlevels the compounds show CNS effects to a significant degree but do notshow undesirable muscle effects to any significant degree. The compoundsbegin to cause muscle effects only when employed in amounts of manytimes those required to activate dopamine release.

Example 4

[0051] Determination of Interaction with Ganglion Receptors

[0052] The determination of the interaction of the compounds withganglionic receptors was carried out in accordance with the techniquesdescribed in U.S. Pat. No. 5,597,919 to Dull et al. The maximalactivation for individual compounds (E_(max)) was determined as apercentage of the maximal activation induced by (S)-(−)-nicotine.Reported E_(max) values represent the amount released relative to(S)-(−)-nicotine on a percentage basis. Low E_(max) values atganglia-type receptors indicate that the compounds of the presentinvention do not induce activation of ganglia-type receptors. Suchpreferable compounds have the capability to activate human CNS receptorswithout activating ganglia-type nicotinic acetylcholine receptors. Thus,there is provided a therapeutic window for utilization in the treatmentof CNS disorders. That is, at certain levels the compounds show CNSeffects to a significant degree but do not show certain undesirable sideeffects to any significant degree. The compounds begin to cause effectsat ganglia only when employed in amounts of many times those required toactivate dopamine release.

Example 5 Preparation of(3-(3-pyridyloxy)-propyl)methylaminehemigalactarate3-Chloro-1-(3-pyridyloxy)propane

[0053] Under a nitrogen atmosphere, a solution of 3-hydroxypyridine(5.00 g, 52.58 mmol) in N,N-dimethylformamide (DMF) (55 mL) was slowlyadded to a cold (0-5° C.), stirring slurry of sodium hydride (2.52 g ofan 80% dispersion in mineral oil, 84.0 mmol) in DMF (10 mL). The mixturewas allowed to warm to ambient temperature and further stirred for 1 h.To this slurry was added 1-choro-3-iodopropane (12.90 g, 63.10 mmol),and the resulting dark-brown mixture was stirred at ambient temperaturefor 48 h. Cold water was added and the mixture was extracted withchloroform (4×100 mL). The combined chloroform extracts were washed withwater (2×50 mL), dried (Na₂SO₄), filtered, and concentrated by rotaryevaporation. Water (150 mL) was added, and the mixture was basified with20% NaOH solution (5.0 mL). The alkaline solution was extracted withmethyl t-butyl ether (MTBE) (5×100 mL). The combined MTBE extracts werewashed with water (4×100 mL), dried (Na₂SO₄), filtered, and concentratedby rotary evaporation to give 4.90 g (54.3%) of an oil.

[0054] (3-(3-Pyridyloxy)propyl)methylamine

[0055] The 3-chloro-1-(3-pyridyloxy)propane (4.90 g, 28.55 mmol) wasdissolved in methanol (60 mL) and added to a 40 wt % solution ofmethylamine (60 mL) in a heavy-walled pressure-tube apparatus. The tubewas sealed and the mixture was stirred and heated at 80° C. for 15 h.After cooling, the mixture was concentrated by rotary evaporation, asaturated NaCl solution (25 mL) was added, and the mixture was basifiedwith 20% NaOH solution (5.0 mL). The mixture was extracted withchloroform (4×30 mL). The combined chloroform extracts were dried(Na₂SO₄), filtered, and concentrated by rotary evaporation to give 3.64g of a brown oil. The product was purified by column chromatography onsilica gel (100 g) eluting with chloroform-methanol-triethylamine(70:30:2.5, v/v/v). Selected fractions containing the product (R_(f)0.30) were combined and concentrated by rotary evaporation. Theresulting residue was dissolved in chloroform (15 mL), dried (Na₂SO₄),filtered, and concentrated by rotary evaporation to give 1.92 g (40.4%)of a brown oil.

[0056] (3-(3-Pyridyloxy)propyl)methylamine Hemigalactarate

[0057] To a solution of (3-(3-pyridyloxy)propyl)methylamine (800.0 mg,4.81 mmol) in ethanol (12 mL) was added galactaric acid (505.7 mg, 2.41mmol). Water (2.5 mL) was added dropwise, while gently warming thelight-yellow solution. To remove some white, insoluble solids, the warmsolution was filtered through a glass wool plug, washing the filter plugwith a warm solution of ethanol-water (4:1, v/v) (4 mL). The filtratewas diluted with ethanol (18 mL), producing a white precipitate. Themixture was allowed to cool to ambient temperature and was furthercooled at 5° C. for 15 h. The precipitate was filtered, washed withethanol (6 mL), vacuum dried at 45° C. for 10 h, followed by furthervacuum drying at ambient temperature for 48 h to give 994.4 mg (76.1%)of an off-white, crystalline powder, mp 161-165.5° C.

[0058] Log P values, which have been used to assess the relativeabilities of compounds to pass across the blood-brain barrier (Hansch,et al., J. Med. Chem. ii:1 (1968)), were calculated according using theCerius² software package Version 3.0 by Molecular Simulations, Inc. Thecompound exhibits a log P of 0.562, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier.

[0059] The compound exhibits a Ki of 13 nM. The low binding constantindicates that the compound exhibits good high affinity binding tocertain CNS nicotinic receptors.

[0060] Dopamine release was measured using the techniques described inU.S. Pat. No. 5,597,919 to Dull et al. Release is expressed as apercentage of release obtained with a concentration of (S)-(−)-nicotineresulting in maximal effects. Reported EC₅₀ values are expressed in nM,and E_(max) values represent the amount released relative to(S)-(−)-nicotine on a percentage basis. The compound exhibits an EC₅₀value of 369 nM and an E_(max) value of 96%, indicating that thecompound effectively induces neurotransmitter release thereby exhibitingknown nicotinic pharmacology.

[0061] Rubidium release was measured using the techniques described inBencherif et al., JPET, 279: 1413-1421 (1996). Reported EC₅₀ values areexpressed in nM, and E_(max) values represent the amount of rubidium ionreleased relative to 300 uM tetranmethylammonium ion, on a percentagebasis. The compound exhibits an EC₅₀ value of 960 nM and an E_(max)value of 83%, indicating that the compound effectively inducesactivation of CNS nicotinic receptors.

[0062] The compound exhibits an E_(max) of 0% at muscle-type receptors,indicating that the compound does not induce activation of muscle-typereceptors. The compound has the capability to activate human CNSreceptors without activating muscle-type nicotinic acetylcholinereceptors. Thus, there is provided a therapeutic window for utilizationin the treatment of CNS disorders. That is, at certain levels thecompound shows CNS effects to a significant degree but do not showundesirable muscle effects to any significant degree. The compoundbegins to cause muscle effects only when employed in amounts of manytimes those required to activate dopamine release.

[0063] The determination of the interaction of the compounds withganglionic receptors was carried out in accordance with the techniquesdescribed in U.S. Pat. No. 5,597,919 to Dull et al. The maximalactivation for individual compounds (E_(max)) was determined as apercentage of the maximal activation induced by (S)-(−)-nicotine.Reported E_(max) values represent the amount released relative to(S)-(−)-nicotine on a percentage basis. The compound exhibits an E_(max)of 93% at ganglionic-type receptors.

[0064] A Gemini Avoidance System (San Diego Instruments) were used toevaluate animals in a passive avoidance experiment. During the period ofhabituation, laboratory rats received a subcutaneous injection ofsaline. On the acquisition day, each rat received a subcutaneousinjection of 0.5 umol/kg scopolamine (or saline in the case of thevehicle control group) 30 minutes prior to being placed in the chambers.Five minutes following scopolamine injection, (or 25 minutes beforebeing placed in the chamber), each rat was administered a subcutaneousinjection with one of four doses of the compound. Thirty minutesfollowing the scopolamine or vehicle injection, each rat was placed inthe brightly illuminated chamber, facing away from the sliding door.After 10 seconds, the door separating the chambers opened allowingaccess to the dark chamber. The time to enter the dark chamber wasmeasured. Immediately upon entering the dark chamber, the rat received amild foot shock (0.5 mAmp) for 2 seconds. Twenty four hours followingtraining, each rat was placed in the light chamber facing away from thesliding door. Thirty seconds later the door was opened and each rat wasallowed to enter the dark chamber. Upon entering the dark chamber thesliding door was closed and the rat was removed from the apparatus (noshock was administered). If the rat did not enter the dark chamberwithin 300 seconds, a ceiling score of 300 seconds was recorded for thatrat, and the rat was removed from the apparatus and returned to its homecage. Statistical differences in latencies (latency during acquisitionand retention trials) were analyzed by Kruskal-Wallis one-way analysisof variance on ranks followed by the either of two-tailed Mann-WhitneyU-test or Newman-Keuls analog test if values of p less than 0.05 wereobtained. The compound, at concentrations of 0.3 to 3 umol/kg, resultedin significant reversal of scopolamine induced amnesia in thestep-through passive avoidance paradigm using laboratory rats. Thus, thecompound has potential cognition enhancing effects, an end-pointrelevant to certain CNS disorders.

Example 6 Preparation of (3-(5-bromo(3-pyridyloxy))propyl)methylaminehemigalactarate

[0065] 5-Bromo-3-hydroxypyridine

[0066] 5-Bromo-3-hydroxypyridine was prepared from 2-furfurylamineaccording to the procedure described in U.S. Pat. No. 4,192,946 toClauson-Kaas et al.

[0067] 3-Bromo-5-(3-chloropropoxy)pyridine

[0068] Under a nitrogen atmosphere, a solution of5-bromo-3-hydroxypyridine (1.90 g, 10.92 mmol) in DMF (10 mL) was slowlyadded over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride(0.52 g of an 80% dispersion in mineral oil, 17.47 mmol) in DMF (14 mL).The mixture was allowed to warm to ambient temperature and furtherstirred for 1 h. To this slurry was added dropwise over 5 min1-choro-3-iodopropane (2.68 g, 13.10 mmol), and the resulting dark-brownmixture was stirred at ambient temperature for 48 h. Cold water (30 mL)was carefully added, followed by saturated NaCl solution (20 mL). Theresulting mixture was extracted with ether (5×25 mL). The combined etherextracts were dried (Na₂SO₄), filtered, and concentrated by rotaryevaporation producing a dark-brown oil (4.07 g). The product was used inthe next step without further purification.

[0069] (3-(5-Bromo(3-pyridyloxy))propyl)methylamine

[0070] Crude 3-bromo-5-(3-chloropropoxy)pyridine (4.07 g) from theprevious step was dissolved in CH₃OH (28 mL) and added to a 40 wt %solution of methylamine (35 mL) in a heavy-walled pressure-tubeapparatus. The tube was sealed and the mixture was stirred and heated at102° C. for 4 h. After cooling, the solution was concentrated by rotaryevaporation, a saturated NaCl solution (15 mL) was added, and themixture was basified with 10% NaOH solution (5 mL). The mixture wasextracted with CHCl₃ (4×30 mL). The combined CHCl₃ extracts were dried(Na₂SO₄), filtered, and concentrated by rotary evaporation to give 2.07g of a brown oil. The product was purified by column chromatography onsilica gel (100 g) eluting with CHCL₃- CH₃OH (9:1, v/v) to removeimpurities, followed by CHCL₃- CH₃OH- Et₃N (75:25:2, v/v/v) to collectthe product. Selected fractions containing the product (R_(f) 0.1 3)were combined and concentrated by rotary evaporation. The resultingbrown oil was dissolved in CHCL₃ (25 mL), dried (Na₂SO₄), filtered, andconcentrated by rotary evaporation to give 0.79 g (29.5% based upon5-bromo-3-hydroxypyridine) of an amber-brown oil, which tended tocrystallize as light amber crystals.

[0071] (3-(5-Bromo(3-pyridyloxy))propyl)methylamine Hemigalactarate

[0072] To a solution of (3-(5-bromo(3-pyridyloxy))propyl)methylamine(0.790 g, 3.22 mmol) in ethanol (12 mL) was added galactaric acid (339.0mg, 1.61 mmol). Water (3.4 mL) was added dropwise, while warming thelight-yellow solution to near reflux. To remove some white, insolublecrystals, the warm solution was filtered through a glass wool plug,washing the filter plug with a warm solution of ethanol-water (4:1, v/v)(3.8 mL). The filtrate was diluted with ethanol (18 mL), producing alight-beige precipitate. The mixture was allowed to cool to ambienttemperature and was further cooled at 5° C. for 48 h. The precipitatewas filtered, washed with ethanol (5 mL), vacuum dried at 40° C. for 24h to give 983.3 mg (68.8%) of a glassy, beige powder, mp 166-173.5° C.

[0073] Log P values, which have been used to assess the relativeabilities of compounds to pass across the blood-brain barrier (Hansch,et al., J. Med. Chem. ii:1 (1968)), were calculated according using theCerius′ software package Version 3.0 by Molecular Simulations, Inc. Thecompound exhibits a log P of 0.662, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier

[0074] The compound exhibits a Ki of 44 nM. The low binding constantindicates that the compound exhibits good high affinity binding tocertain CNS nicotinic receptors.

Example 7 Synthesis of 2-(3-Pyridyloxy)ethylamine Hemigalactarate

[0075] 2-Chloro-1-(3-pyridyloxy)ethane

[0076] Under a nitrogen atmosphere, a solution of 3-hydroxypyridine(12.00 g, 126.18 mmol) in N, N-dimethylformamide (DMF) (63 mL) was addeddrop-wise over 25 min to a cold (0-5° C.), stirring slurry of sodiumhydride (6.17 g of an 80% dispersion in mineral oil, 205.7 mmol) in DMF(130 mL). The mixture was allowed to stir and warm to ambienttemperature over 1 h. Next, 1-bromo-2-chloroethane (21.71 g, 151.37mmol) was added drop-wise over 45 min. The resulting dark-brown mixturewas stirred at ambient temperature for 24 h. Gas chromatographicanalysis indicated an incomplete reaction; therefore, more1-bromo-2-chloroethane (8.65 g, 60.3 mmol) and sodium hydride (2.09 g ofan 80% dispersion in mineral oil, 69.7 mmol) were added. The mixture wasstirred at ambient temperature for 40 h. Water (60 mL) was carefullyadded over 30 min, followed by saturated NaCl solution (40 mL), and themixture was extracted with ether (6×50 mL). The combined orange-yellowether extracts were washed with saturated NaCl solution (75 mL). Theether layer was dried (Na₂SO₄), filtered, and concentrated by rotaryevaporation to a residue that was dried briefly under high vacuum togive 2.87 g (14.4%) of a light-brown oil.

[0077] 2-(3-Pyridyloxy)ethylamine

[0078] The 2-chloro-1-(3-pyridyloxy)ethane (1.23 g, 7.80 mmol) wasdissolved in methanol (25 mL) and added to concentrated ammoniumhydroxide solution (29.7%, 14.8 M, 55 mL) in a heavy-walled glasspressure-tube apparatus. The tube was sealed and the mixture was stirredand heated at 125° C. (oil bath temperature) for 42 h. After cooling,the mixture was concentrated by rotary evaporation. Saturated NaClsolution (10 mL) was added to the residue, and the solution (pH 6) wasextracted with ether (3×25 mL) to remove impurities. The aqueous layerwas diluted with saturated NaCl solution (15 mL) and basified to pH 12with 10% NaOH solution (5 mL). The mixture was extracted with chloroform(4×50 mL). The combined light-yellow chloroform extracts were dried(Na₂SO₄), filtered, and concentrated by rotary evaporation to a residuethat was dried briefly under high vacuum to give 0.390 g (36.2%) of alight-yellow oil.

[0079] 2-(3-Pyridyloxy)ethylamine Hemigalactarate

[0080] To a solution of 2-(3-pyridyloxy)ethylamine (0.390 g, 2.823 mmol)in ethanol (6 mL) was added galactaric acid (0.276 g, 1.312 mmol). Water(1.7 mL) was added drop-wise, while warming the solution to reflux. Toremove some white, insoluble solids, the warm solution was filteredthrough a glass wool plug, washing the filter plug with a warm solutionof ethanol-water (4:1, v/v) (1.9 mL). The filtrate was diluted withethanol (9 mL). The mixture was allowed to cool to ambient temperatureand was further cooled at 5° C. for 12 days. The product hadprecipitated as a semi-crystalline oil. The solvent was removed byrotary evaporation, and the resulting solids were vacuum dried at 40° C.for 24 h. The resulting solids were slurried in 2-propanol, andsubsequently diluted with anhydrous ether. The solids were filtered,washed with ether, and vacuum dried at 40° C. for 24 h to give 0.598 g(87.1%) of a fluffy, off-white powder, mp 151-156° C. The compoundexhibits a Ki of 1600 nM. The compound exhibits neurotransmitter releaseof 30 percent.

Example 8 Synthesis of Methyl(2-(3-pyridyloxy)ethyl)amineHemigalactarate

[0081] 2-Chloro-1-(3-pyridyloxy)ethane

[0082] Under a nitrogen atmosphere, a solution of 3-hydroxypyridine(2.00 g, 21.0 mmol) in N, N-dimethylformamide (DMF) (10 mL) was addeddrop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodiumhydride (0.756 g of an 80% dispersion in mineral oil, 27.5 mmol) in DMF(15 mL). The mixture was allowed to stir and warm to ambient temperatureover 1 h. Next, 1-bromo-2-chloroethane (3.60 g, 25.2 mmol) was addeddrop-wise over 5 min. The resulting dark-brown mixture was stirred atambient temperature for 4 h. Water (30 mL) was added, followed bysaturated NaCl solution (25 mL), and the mixture was extracted withether (4×50 mL). The combined ether extracts were dried (Na₂SO₄),filtered, and concentrated by rotary evaporation to a residue that wasdried briefly under high vacuum to give 3.96 g (66.1%) of a light-brownoil.

[0083] Methyl(2-(3-pyridyloxy)ethyl)amine

[0084] The 2-chloro-1-(3-pyridyloxy)ethane (2.17 g, 13.8 mmol) wasdissolved in methanol (25 mL) and added to a 40 wt % aqueous solution ofmethylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. Thetube was sealed and the mixture was stirred and heated at 100° C. (oilbath temperature) for 4 h. After cooling, the mixture was concentratedby rotary evaporation. Saturated NaCl solution (25 mL) was added to theresidue. The pH was adjusted to 1 with 10% HCl solution and impuritieswere extracted with chloroform (2×50 mL). The pH of the aqueous phasewas raised to 6 with 100% NaOH solution and other impurities wereextracted with ether (3×25 mL). The aqueous layer was basified to pH 10with 10% NaOH solution and extracted with chloroform (4×50 mL). Thecombined chloroform extracts were dried (Na₂SO₄), filtered, andconcentrated by rotary evaporation to a residue that was dried brieflyunder high vacuum to give 0.253 g (12.0%) of an oil.

[0085] Methyl(2-(3-pyridyloxy)ethyl)amine Hemigalactarate

[0086] To a solution of methyl(2-(3-pyridyloxy)ethyl)amine (0.233 g,1.53 mmol) in ethanol (4 mL) was added galactaric acid (0.161 g, 0.775mmol). Water (1 mL) was added drop-wise, while warming the solution toreflux. To remove some white, insoluble solids, the warm solution wasfiltered through a glass wool plug, washing the filter plug with a warmsolution of ethanol-water (4:1, v/v). The filtrate was diluted withethanol (20 mL). The mixture was allowed to cool to ambient temperatureand was further cooled at 5° C. for 48 h. The resulting solids werefiltered, washed with cold ethanol (4 mL), and vacuum dried at 40° C. togive 0.307 g (77.9%) of a white to off-white, crystalline powder, mp148.5-151.5° C. (d). The compound exhibits a Ki of 65 nM; the effect atmuscle sites is 0 percent; and the effect at ganglia sites is 0 percent.The compound exhibits neurotransmitter release of 143 percent.

Example 9 Synthesis of Dimethyl(2-(3-pyridyloxy)ethylamineHemigalactarate

[0087] 2-Chloro-1-(3-pyridyloxy)ethane

[0088] Under a nitrogen atmosphere, a solution of 3-hydroxypyridine(12.00 g, 126.18 mmol) in N, N-dimethylformamide (DMF) (63 mL) was addeddrop-wise over 25 min to a cold (0-5° C.), stirring slurry of sodiumhydride (6.17 g of an 80% dispersion in mineral oil, 205.7 mmol) in DMF(130 mL). The mixture was allowed to stir and warm to ambienttemperature over 1 h. Next, 1-bromo-2-chloroethane (21.71 g, 151.37mmol) was added drop-wise over 45 min. The resulting dark-brown mixturewas stirred at ambient temperature for 24 h. Gas chromatographicanalysis indicated an incomplete reaction; therefore, more1-bromo-2-chloroethane (8.65 g, 60.3 mmol) and sodium hydride (2.09 g ofan 80% dispersion in mineral oil, 69.7 mmol) were added. The mixture wasstirred at ambient temperature for 40 h. Water (60 mL) was carefullyadded over 30 min, followed by saturated NaCl solution (40 mL), and themixture was extracted with ether (6×50 mL). The combined orange-yellowether extracts were washed with saturated NaCl solution (75 mL). Theether layer was dried (Na₂SO₄), filtered, and concentrated by rotaryevaporation to a residue that was dried briefly under high vacuum togive 2.87 g (14.4%) of a light-brown oil.

[0089] Dimethyl(2-(3-pyridyloxy)ethylamine

[0090] The 2-chloro-1-(3-pyridyloxy)ethane (2.21 g, 10.41 mmol) wasdissolved in methanol (14 mL) and added to a 40 wt % aqueous solution ofdimethylamine (22 mL) in a heavy-walled glass pressure-tube apparatus.The tube was sealed and the mixture was stirred and heated at 100° C.(oil bath temperature) for 4 h. After cooling, the mixture wasconcentrated by rotary evaporation. Saturated NaCl solution (7 mL) and10% NaOH solution were added to the residue (brown liquid), giving pH12. The mixture was extracted with chloroform (4×20 mL). The combinedchloroform extracts were dried (Na₂SO₄), filtered, and concentrated byrotary evaporation to a residue that was dried briefly under high vacuumto give 1.184 g of a brown oil. Further purification was accomplished asfollows: The oil was diluted with water (10 mL) and acidified to pH 6with 10% HCl solution (6 mL). The mixture was extracted with ether (3×25mL) to remove impurities. The aqueous phase was treated with saturatedNaCl solution (15 mL) and basified with 10% NaOH solution to pH 12. Theproduct was extracted with chloroform (4×20 mL). The combinedlight-yellow chloroform extracts were dried (Na₂SO₄), filtered, andconcentrated by rotary evaporation to a residue that was dried brieflyunder high vacuum to give 0.727 g (42.0%) of a light-yellow oil.

[0091] Dimethyl(2-(3-pyridyloxy)ethylamine Hemigalactarate

[0092] To a solution of dimethyl(2-(3-pyridyloxy)ethylamine (0.727 g,4.37 mmol) in ethanol (11 mL) was added galactaric acid (0.46 g, 2.19mmol). Water (3.5 mL) was added drop-wise, while warming the solution toreflux. To remove some white, insoluble solids, the warm solution wasfiltered through a glass wool plug, washing the filter plug with a warmsolution of ethanol-water (4:1, v/v) (3.5 mL). The filtrate was dilutedwith ethanol (17 mL). The mixture was allowed to cool to ambienttemperature and was further cooled at 5° C. for 10 days. Very few solidsprecipitated. Consequently, the solution was concentrated to a residuethat was vacuum dried for 20 h. The solids were slurried in 2-propanoland diluted with anhydrous ether. The precipitate was filtered, washedwith ether, and vacuum dried at 40° C. to give 0.818 g (68.9%) of anoff-white, slightly beige powder, mp 113-117° C. The compound exhibits aKi of 151 nM; the effect at muscle sites is 0 percent; and the effect atganglia sites is 0 percent. The compound exhibits neurotransmitterrelease of 0 percent.

Example 10 Synthesis of 3-(3-Pyridyloxy)propylamine Hemigalactarate

[0093] 3-Chloro-1-(3-pyridyloxy)propane

[0094] Under a nitrogen atmosphere, a solution of 3-hydroxypyridine(35.00 g, 0.368 mmol) in N,N-dimethylformamide (DMF) (150 mL) was slowlyadded drop-wise over 15 min to a cold (0-5° C.), stirring slurry ofsodium hydride (17.64 g of an 80% dispersion in mineral oil, 0.588 mol)in DMF (250 mL). The mixture was allowed to stir and warm to ambienttemperature over 1 h. The gray slurry was cooled to 0-5° C., and1-chloro-3-iodopropane (90.3 g, 0.442 mol) was added drop-wise over 30min. The resulting dark-brown mixture was allowed to stir and warm toambient temperature over 16 h. Water (500 mL) was added and the mixturewas divided into equal parts. Each half was diluted with saturated NaClsolution (200 mL) and extracted with ether (5×200 mL). All etherextracts were combined and concentrated to give 55.1 g (87.3%) of adark-brown oil.

[0095] 3-(3-Pyridyloxy)propylamine

[0096] The 3-chloro-1-(3-pyridyloxy)propane (1.98 g, 11.6 mmol) wasdissolved in methanol (25 mL) and added to concentrated ammoniumhydroxide solution (29.7%, 14.8 M, 55 mL) in a heavy-walled glasspressure-tube apparatus. The tube was sealed and the mixture was stirredand heated at 100° C. (oil bath temperature) for 6 h. After cooling, themixture was concentrated by rotary evaporation. Saturated NaCl solution(10 mL) was added to the residue, and the solution (pH 6) was extractedwith ether (3×25 mL) to remove impurities. The aqueous layer wasbasified to pH 10 with 10% NaOH solution, and the mixture was extractedwith chloroform (4×25 mL). The combined chloroform extracts were dried(Na₂SO₄), filtered, and concentrated by rotary evaporation to a residuethat was dried briefly under high vacuum to give 0.354 g (20.1%) of anoil.

[0097] 3-(3-Pyridyloxy)propylamine Hemigalactarate

[0098] To a solution of 3-(3-pyridyloxy)propylamine (0.354 g, 2.30 mmol)in ethanol (5 mL) was added galactaric acid (0.244 g, 1.16 mmol). Water(1.5 mL) was added drop-wise, while warming the solution to reflux. Toremove some white, insoluble solids, the warm solution was filteredthrough a glass wool plug, washing the filter plug with a warm solutionof ethanol-water (4:1, v/v). The filtrate was diluted with ethanol (25mL). The mixture was allowed to cool to ambient temperature and wasfurther cooled at 5° C. for 16 h. The solids were filtered, washed withcold ethanol (5 mL), and vacuum dried at 40° C. to give 344.8 mg (58.3%)of light-yellow crystals, mp 176-178° C. The compound exhibits a Ki of65 nM; the effect at muscle sites is 0 percent; and the effect atganglia sites is 0 percent. The compound exhibits a Ki of 12 nM; theeffect at muscle sites is 0 percent; and the effect at ganglia sites is0 percent. The compound exhibits neurotransmitter release of 0 percent.

Example 11 Synthesis of Dimethyl(3-(3-pyridyloxy)propyl)amineHemigalactarate

[0099] 3-Chloro-1-(3-pyridyloxy)propane

[0100] Under a nitrogen atmosphere, a solution of 3-hydroxypyridine(35.00 g, 0.368 mmol) in N,N-dimethylformamide (DMF) (150 mL) was slowlyadded drop-wise over 15 min to a cold (0-5° C.), stirring slurry ofsodium hydride (17.64 g of an 80% dispersion in mineral oil, 0.588 mol)in DMF (250 mL). The mixture was allowed to stir and warm to ambienttemperature over 1 h. The gray slurry was cooled to 0-5° C., and1-chloro-3-iodopropane (90.3 g, 0.442 mol) was added drop-wise over 30min. The resulting dark-brown mixture was allowed to stir and warm toambient temperature over 16 h. Water (500 mL) was added and the mixturewas divided into equal parts. Each half was diluted with saturated NaClsolution (200 mL) and extracted with ether (5×200 mL). All etherextracts were combined and concentrated to give 55.1 g (87.3%) of adark-brown oil.

[0101] Dimethyl(3-(3-pyridyloxy)propyl)amine

[0102] The 3-chloro-1-(3-pyridyloxy)propane (2.00 g, 11.65 mmol) wasdissolved in methanol (25 mL) and added to a 40 wt % aqueous solution ofdimethylamine (50 mL) in a heavy-walled glass pressure-tube apparatus.The tube was sealed and the mixture was stirred and heated at 100° C.(oil bath temperature) for 4 h. After cooling, the mixture wasconcentrated by rotary evaporation. Saturated NaCl solution (25 mL) wasadded to the residue. The pH of the solution was adjusted to 6, and themixture was extracted with ether (3×25 mL) to remove impurities. Theaqueous layer was basified to pH 10 with 100% NaOH solution andextracted with chloroform (4×50 mL). The combined chloroform extractswere dried (Na₂SO₄), filtered, and concentrated to give 1.95 g (92.9%)of an oil.

[0103] Dimethyl(3-(3-pyridyloxy)propyl)amine Hemigalactarate

[0104] To a solution of dimethyl(3-(3-pyridyloxy)propyl)amine (1.95 g,10.8 mmol) in ethanol (15 mL) was added galactaric acid (0.696 g, 3.30mmol). Water (4 mL) was added drop-wise, while warming the solution toreflux. To remove some white, insoluble solids, the warm solution wasfiltered through a glass wool plug, washing the filter plug with a warmsolution of ethanol-water (4:1, v/v). The filtrate was diluted withethanol (80 mL). The mixture was allowed to cool to ambient temperatureand was further cooled at 5° C. for 16 h. No solids precipitated.Consequently, the solution was concentrated to a crystalline solid. Thesolid was slurried in ether, filtered, washed with ether, and vacuumdried at 40° C. to give 1.94 g (62.7%) of brown powdery crystals, mp137-140° C. The compound exhibits a Ki of 126 nM; the effect at musclesites is 8 percent; and the effect at ganglia sites is 5 percent. Thecompound exhibits neurotransmitter release of 32 percent.

Example 12 Synthesis of 4-(3-Pyridyloxy)butylamine Hemigalactarate

[0105] 4-Chloro-1-(3-pyridyloxy)butane

[0106] Under a nitrogen atmosphere, a solution of 3-hydroxypyridine(3.50 g, 36.8 mmol) in N, N-dimethylformamide (DMF) (10 mL) was addeddrop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodiumhydride (1.16 g of an 80% dispersion in mineral oil, 38.6 mmol) in DMF(40 mL). The mixture was allowed to stir and warm to ambient temperatureover 1 h. The mixture was then cooled to 0-5° C., and1-chloro4-iodobutane (9.67 g, 44.2 mmol) was added drop-wise over 5 min.The resulting dark-brown mixture was stirred at ambient temperature for2 h. Water (25 mL) was added, followed by saturated NaCl solution (25mL), and the mixture was extracted with ether (4×50 mL). The combinedether extracts were dried (Na₂SO₄), filtered, and concentrated by rotaryevaporation to a residue that was dried briefly under high vacuum togive 6.89 g (quantitative yield) of an oil.

[0107] 4-(3-Pyridyloxy)butylamine

[0108] The 4-chloro-1-(3-pyridyloxy)butane (2.00 g, 10.8 mmol) wasdissolved in methanol (25 mL) and added to concentrated ammoniumhydroxide solution (29.7%, 14.8 M, 50 mL) in a heavy-walled glasspressure-tube apparatus. The tube was sealed and the mixture was stirredand heated at 100° C. (oil bath temperature) for 6 h. After cooling, themixture was concentrated by rotary evaporation. Saturated NaCl solution(10 mL) was added to the residue, and the solution (pH 6) was extractedwith ether (3×25 mL) to remove impurities. The aqueous layer wasbasified to pH 10 with 10% NaOH solution, and the mixture was extractedwith chloroform (4×25 mL). The combined chloroform extracts were dried(Na₂SO₄), filtered, and concentrated by rotary evaporation to a residuethat was dried briefly under high vacuum to give 1.25 g (74.2%) of anoil.

[0109] 4-(3-Pyridyloxy)butylamine Hemigalactarate

[0110] To a solution of 4-(3-pyridyloxy)butylamine (1.25 g, 7.50 mmol)in ethanol (12 mL) was added galactaric acid (0.791 g, 3.76 mmol). Water(3 mL) was added drop-wise, while warming the solution to reflux. Toremove some white, insoluble solids, the warm solution was filteredthrough a glass wool plug, washing the filter plug with a warm solutionof ethanol-water (4:1, v/v) (4 mL). The filtrate was diluted withethanol (30 mL). The mixture was allowed to cool to ambient temperatureand was further cooled at 5° C. for 48 h. Very few solids precipitated.Consequently, the solution was concentrated to a flaky solid. Theproduct was slurried in 2-propanol, and the 2-propanol was decanted. Theproduct was vacuum dried at 40° C. to give 1.28 g (62.7%) of fine, whitepowder, mp 177-180° C. The compound exhibits a Ki of 232 nM; the effectat muscle sites is 0 percent; and the effect at ganglia sites is 11percent. The compound exhibits neurotransmitter release of 100 percent.

Example 13 Synthesis of Methyl(4-(3-pyridyloxy)butyl)amineHemigalactarate

[0111] 4-Chloro-1-(3-pyridyloxy)butane

[0112] Under a nitrogen atmosphere, a solution of 3-hydroxypyridine(3.50 g, 36.8 mmol) in N, N-dimethylformamide (DMF) (10 mL) was addeddrop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodiumhydride (1.16 g of an 80% dispersion in mineral oil, 38.6 mmol) in DMF(40 mL). The mixture was allowed to stir and warm to ambient temperatureover 1 h. The mixture was then cooled to 0-5° C., and1-chloro-4-iodobutane (9.67 g, 44.2 mmol) was added drop-wise over 5min. The resulting dark-brown mixture was stirred at ambient temperaturefor 2 h. Water (25 mL) was added, followed by saturated NaCl solution(25 mL), and the mixture was extracted with ether (4×50 mL). Thecombined ether extracts were dried (Na₂SO₄), filtered, and concentratedby rotary evaporation to a residue that was dried briefly under highvacuum to give 6.89 g (quantitative yield) of an oil.

[0113] Methyl(4-(3-pyridyloxy)butyl)amine

[0114] The 4-chloro-1-(3-pyridyloxy)butane (2.00 g, 10.8 mmol) wasdissolved in methanol (25 mL) and added to a 40 wt % aqueous solution ofmethylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. Thetube was sealed and the mixture was stirred and heated at 100° C. (oilbath temperature) for 4 h. After cooling, the mixture was concentratedby rotary evaporation. Saturated NaCl solution (10 mL) was added to theresidue, and the solution (pH 6) was extracted with ether (3×25 mL) toremove impurities. The aqueous layer was basified to pH 10 with 10% NaOHsolution, and the mixture was extracted with chloroform (4×25 mL). Thecombined chloroform extracts were dried (Na₂SO₄), filtered, andconcentrated by rotary evaporation to a residue that was dried brieflyunder high vacuum to give 1.47 g (75.5%) of an oil.

[0115] Methyl(4-(3-pyridyloxy)butyl)amine Hemigalactarate

[0116] To a solution of methyl(4-(3-pyridyloxy)butyl)amine (1.25 g, 7.50mmol) in ethanol (15 mL) was added galactaric acid (0.858 g, 4.08 mmol).Water (4 mL) was added drop-wise, while warming the solution to reflux.To remove some white, insoluble solids, the warm solution was filteredthrough a glass wool plug, washing the filter plug with a warm solutionof ethanol-water (4:1, v/v) (4 mL). The filtrate was diluted withethanol (40 mL). The mixture was allowed to cool to ambient temperatureand was further cooled at 5° C. for 16 h. The solids were filtered,washed with cold ethanol and vacuum dried at 40° C. to give 1.69 g(72.8%) of a fine, white, crystalline powder, mp 173-1 75° C. Thecompound exhibits a Ki of 5523 nM. The compound exhibitsneurotransmitter release of 56 percent.

Example 14 Synthesis of Dimethyl(4-(3-pyridyloxy)butyl)amineHemigalactarate

[0117] 4-Chloro-1-(3-pyridyloxy)butane

[0118] Under a nitrogen atmosphere, a solution of 3-hydroxypyridine(3.50 g, 36.8 mmol) in N, N-dimethylformamide (DMF) (10 mL) was addeddrop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodiumhydride (1.16 g of an 80% dispersion in mineral oil, 38.6 mmol) in DMF(40 mL). The mixture was allowed to stir and warm to ambient temperatureover 1 h. The mixture was then cooled to 0-5° C., and1-chloro-4-iodobutane (9.67 g, 44.2 mmol) was added drop-wise over 5min. The resulting dark-brown mixture was stirred at ambient temperaturefor 2 h. Water (25 mL) was added, followed by saturated NaCl solution(25 mL), and the mixture was extracted with ether (4×50 mL). Thecombined ether extracts were dried (Na₂SO₄), filtered, and concentratedby rotary evaporation to a residue that was dried briefly under highvacuum to give 6.89 g (quantitative yield) of an oil.

[0119] Dimethyl(4-(3-pyridyloxy)butyl)amine

[0120] A portion of the 4-chloro-1-(3-pyridyloxy)butane was dissolved inmethanol (25 mL) and added to a 40 wt % aqueous solution ofdimethylamine (50 mL) in a heavy-walled glass pressure-tube apparatus.The tube was sealed and the mixture was stirred and heated at 100° C.(oil bath temperature) for 4 h. After cooling, the mixture wasconcentrated by rotary evaporation. Saturated NaCl solution (10 mL) wasadded to the residue, and the solution (pH 6) was extracted with ether(3×25 mL) to remove impurities. The aqueous layer was basified to pH 10with 10% NaOH solution, and the mixture was extracted with chloroform(4×25 mL). The combined chloroform extracts were dried (Na₂SO₄),filtered, and concentrated by rotary evaporation to a residue that wasdried briefly under high vacuum to give 1.26 g of an oil.

[0121] Dimethyl(4-(3-pvridyloxy)butyl)amine Hemigalactarate

[0122] To a solution of dimethyl(4-(3-pyridyloxy))butylamine (1.26 g,6.49 mmol) in ethanol (10 mL) was added galactaric acid (0.682 g, 3.25mmol). Water (3 mL) was added drop-wise, while warming the solution toreflux. To remove some white, insoluble solids, the warm solution wasfiltered through a glass wool plug, washing the filter plug with a warmsolution of ethanol-water (4:1, v/v) (4 mL). The filtrate was dilutedwith ethanol (80 mL). The mixture was allowed to cool to ambienttemperature and was further cooled at 5° C. for 16 h. Very few solidsprecipitated. Consequently, the solution was concentrated, and theresidue was slurried in ether. The solids were filtered, washed withether and vacuum dried at 40° C. to give 1.06 g (54.7%) of alight-brown, flaky powder, mp 127-130° C. The compound exhibits a Ki of3410 nM. The compound exhibits neurotransmitter release of 24 percent.

Example 15 Synthesis of 3-(5-Chloro-3-pyridyloxy)propylamineHemigalactarate

[0123] 3-Chloro-5-(3-chloropropoxy)pyridine

[0124] Under a nitrogen atmosphere, a solution of 5-chloro-3-pyridinol(15.00 g, 115.8 mmol) in N, N-dimethylformamide (DMF) (10 mL) was addeddrop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodiumhydride (3.69 g of an 80% dispersion in mineral oil, 123.0 mmol) in DMF(15 mL). The mixture was allowed to stir and warm to ambient temperatureover 1 h. Next, 1-chloro-3-iodopropane (28.4 g, 138.9 mmol) was addeddrop-wise over 5 min. The resulting dark-brown mixture was stirred atambient temperature for 4 h. Water (25 mL) was added, followed bysaturated NaCl solution (25 mL), and the mixture was extracted withether (4×50 mL). The combined ether extracts were dried (Na₂SO₄),filtered, and concentrated by rotary evaporation to a residue that wasdried briefly under high vacuum to give 17.22 g (73.0%) of an oil.

[0125] 3-(5-Chloro-3-pyridyloxy)propylamine

[0126] The 3-chloro-5-(3-chloropropoxy)pyridine (5.74 g, 28.0 mmol) wasdissolved in methanol (25 mL) and added to concentrated ammoniumhydroxide solution (29.7%, 14.8 M, 55 mL) in a heavy-walled glasspressure-tube apparatus. The tube was sealed and the mixture was stirredand heated at 10° C. (oil bath temperature) for 6 h. After cooling, themixture was concentrated by rotary evaporation. Saturated NaCl solution(10 mL) was added to the residue, and the solution (pH 6) was extractedwith ether (3×25 mL) to remove impurities. The aqueous layer wasbasified to pH 10 with 10% NaOH solution, and the mixture was extractedwith chloroform (4×25 mL). The combined chloroform extracts were dried(Na₂SO₄), filtered, and concentrated by rotary evaporation to a residuethat was dried briefly under high vacuum to give 3.30 g (63.4%) of anoil.

[0127] 3-(5-Chloro-3-pyridyloxy)propylamine Hemigalactarate

[0128] To a solution of 3-(5-chloro-3-pyridyloxy)propylamine (1.00 g,5.38 mmol) in ethanol (12 mL) was added galactaric acid (0.564 g, 2.688mmol). Water (3 mL) was added drop-wise, while warming the solution toreflux. To remove some white, insoluble solids, the warm solution wasfiltered through a glass wool plug, washing the filter plug with a warmsolution of ethanol-water (4:1, v/v) (4 mL). The filtrate was dilutedwith ethanol (80 mL). The mixture was allowed to cool to ambienttemperature and was further cooled at 5° C. for 48 h. No solids hadformed. Consequently, the solution was concentrated to a residue thatwas vacuum dried. The solids were slurried in 2-propanol, and the2-propanol was evaporated. The resulting solids were slurried inanhydrous ether. The product was filtered, washed with ether and vacuumdried at 40° C. to give 0.996 g (63.5%) of a brown, flaky powder, mp170-173° C. The compound exhibits a Ki of 46 nM; the effect at musclesites is 0 percent; and the effect at ganglia sites is 4 percent. Thecompound exhibits neurotransmitter release of 110 percent.

Example 16 Synthesis of (3-(5-Chloro(3-pyridyloxy))propyl)methylamineHemigalactarate

[0129] 3-Chloro-5-(3-chloropropoxy)pyridine

[0130] Under a nitrogen atmosphere, a solution of 5-chloro-3-pyridinol(15.00 g, 115.8 mmol) in N, N-dimethylformamide (DMF) (10 mL) was addeddrop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodiumhydride (3.69 g of an 80% dispersion in mineral oil, 123.0 mmol) in DMF(15 mL). The mixture was allowed to stir and warm to ambient temperatureover 1 h. Next, 1-chloro-3-iodopropane (28.4 g, 138.9 mmol) was addeddrop-wise over 5 min. The resulting dark-brown mixture was stirred atambient temperature for 4 h. Water (25 mL) was added, followed bysaturated NaCl solution (25 mL), and the mixture was extracted withether (4×50 mL). The combined ether extracts were dried (Na₂SO₄),filtered, and concentrated by rotary evaporation to a residue that wasdried briefly under high vacuum to give 17.22 g (73.0%) of an oil.

[0131] 3-(5-Chloro(3-pyridyloxy))propyl)methylamine

[0132] The 3-chloro-5-(3-chloropropoxy)pyridine (5.74 g, 28.0 mmol) wasdissolved in methanol (25 mL) and added to a 40 wt % aqueous solution ofmethylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. Thetube was sealed and the mixture was stirred and heated at 100° C. (oilbath temperature) for 4 h. After cooling, the mixture was concentratedby rotary evaporation. Saturated NaCl solution (25 mL) was added to theresidue. The pH of the solution was adjusted to 6, and impurities wereextracted with ether (3× 15 mL). The aqueous layer was basified to pH 10with 10% NaOH solution and extracted with chloroform (4×15 mL). Thecombined chloroform extracts were dried (Na₂SO₄), filtered, andconcentrated by rotary evaporation to a residue that was dried brieflyunder high vacuum to give 4.02 g (71.8%) of an oil.

[0133] (3-(5-Chloro(3-pyridyloxy))propyl)methylamine Hemigalactarate

[0134] To a solution of (3-(5-chloro(3-pyridyloxy))propyl)methylamine(1.00 g, 5.00 mmol) in ethanol (12 mL) was added galactaric acid (0.791g, 3.76 mmol). Water (3 mL) was added drop-wise, while warming thesolution to reflux. To remove some white, insoluble solids, the warmsolution was filtered through a glass wool plug, washing the filter plugwith a warm solution of ethanol-water (4:1, v/v) (4 mL). The filtratewas diluted with ethanol (30 mL). The mixture was allowed to cool toambient temperature and was further cooled at 5° C. for 48 h. The solidswere filtered, washed and vacuum dried at 40° C. to give 1.163 g (76.3%)of off-white, powdery crystals, mp 173-174° C. The compound exhibits aKi of 11 nM; the effect at muscle sites is 16 percent; and the effect atganglia sites is 7 percent. The compound exhibits neurotransmitterrelease of 100 percent.

Example 17 Synthesis of Methyl(3-(5-methoxy-3-pyridyloxy)propyl)amineHemigalactarate

[0135] 5-Bromo-3-methoxypyridine

[0136] This compound was prepared in 64.7% yield as a white, crystallinepowder (mp 28-30° C.) using the general procedure of D. L. Comins and M.O. Killpack, J. Org. Chem. 55: 69-73 (1990).

[0137] 5-Methoxy-3-pyridylamine

[0138] Crude 5-bromo-3-methoxypyridine (3.50 g, 18.62 mmol) wasdissolved in methanol (50 mL) and added to concentrated ammoniumhydroxide (29.7%, 14.8 M, 50 mL) and copper(l) bromide (2.67 g, 18.62mmol) in a heavy-walled glass pressure-tube apparatus. The tube wasflushed with nitrogen and sealed. The mixture was stirred and heated at170-172° C. (oil bath temperature) for 24 h. After cooling, the solutionwas concentrated by rotary evaporation to a gummy residue. The residuewas diluted with sodium carbonate solution (17.6%, 200 mL) and extractedwith CH₂Cl₂ (4×50 mL). The combined CH₂Cl₂ extracts were dried (MgSO₄),filtered, and concentrated by rotary evaporation to give 1.26 g of acream-brown solid. The aqueous phase was re-extracted with CH₂Cl₂ (4×50mL). The combined CH₂Cl₂ extracts were similarly dried and concentratedto give an additional 0.34 g of a cream-brown solid, bringing the totalyield to 1.60 g (69.2%).

[0139] 5-Methoxypyridin-3-ol

[0140] A mixture of concentrated sulfuric acid (18 M, 2.83 mL), water(3.84 mL) and crushed ice (6.60 g) was added to 5-methoxy-3-pyridylamine(1.64 g, 13.23 mmol). The cold mixture (0-5° C.) was stirred for 10 minand a solution of sodium nitrite (0.91 g, 13.23 mmol) in water (2.7 mL)was then added. After stirring for 10 min, a boiling solution ofconcentrated sulfuric acid (8.6 mL) and water (6.6 mL) was added. Themixture was heated until all solids dissolved. Ice (5.0 g) was added tocool the solution. The pH was adjusted to 8 with 10% NaOH solution.Saturated NaCl solution (100 mL) was added, and the mixture wasextracted with ethyl acetate (4×100 mL). The combined ethyl acetateextracts were dried (MgSO₄), filtered and concentrated by rotaryevaporation to give 0.50 g (30.1%) of a brown oil.

[0141] 5-(3-Chloropropoxy)-3-methoxypyridine

[0142] Under a nitrogen atmosphere, a solution of 5-methoxypyridin-3-ol(0.50 g, 4.01 mmol) in DMF (10 mL) was slowly added over 10 min to acold (0-5° C.), stirring slurry of sodium hydride (0.19 g of an 80%dispersion in mineral oil, 6.33 mmol) in DMF (15 mL). The mixture wasallowed to warm to ambient temperature and further stirred for 1 h. Tothis slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (0.98g, 4.81 mmol), and the resulting dark brown mixture was stirred atambient temperature for 4 h. Cold water (25 mL) was carefully added,followed by saturated NaCl solution (25 mL). The resulting mixture wasextracted with ether (4×50 mL). The combined ether extracts were dried(MgSO₄), filtered, and concentrated by rotary evaporation producing adark-brown oil (0.75 g, 92.8%).

[0143] Methyl(3-(5-methoxy-3-pyridyloxy)propyl)amine

[0144] Crude 5-(3-chloropropoxy)-3-methoxypyridine (0.75 g, 3.73 mmol)was dissolved in methanol (10.5 mL) and added to a 40 wt % aqueoussolution of methylamine (10.6 mL) in a heavy-walled glass pressure-tubeapparatus. The tube was sealed and the mixture was stirred and heated at100° C. (oil bath temperature) for 4 h. After cooling, the solution wasconcentrated by rotary evaporation. Saturated NaCl solution (50 mL) wasadded, and the mixture was basified with 10% NaOH solution to pH 11. Themixture was extracted with ether (4×50 mL). The combined ether extractswere dried (MgSO₄), filtered and concentrated by rotary evaporation togive 0.54 g of a brown oil. The product was purified by columnchromatography on silica gel (18 g) eluting with CHCl₃-CH₃OH (1:1, v/v)to remove impurities, followed by CHCl₃-CH₃OH-Et₃N (50:50:2, v/v/v) tocollect the product. Selected fractions containing the product werecombined and concentrated by rotary evaporation. The resulting brown oilwas dissolved in CHCl₃ (25 mL), dried (MgSO₄), filtered, andconcentrated by rotary evaporation to give 0.228 g (31.2%) of a brownoil.

[0145] Methyl(3-(5-methoxy-3-pyridyloxy)propyl)amine Hemigalactarate

[0146] To a solution of methyl(3-(5-methoxy-3-pyridyloxy)propyl)amine(0.228 g, 1.16 mmol) in ethanol (4.3 mL) was added galactaric acid(122.0 mg, 0.58 mmol). Water (1.2 mL) was added drop-wise, while warmingthe solution to near reflux. To remove some white, insoluble crystals,the warm solution was filtered through a glass wool plug, washing thefilter plug with a warm solution of ethanol-water (4:1, v/v) (1.4 mL).The filtrate was diluted with ethanol (6.5 mL), producing a whiteprecipitate. The mixture was allowed to cool to ambient temperature andwas further cooled at 5° C. for 48 h. The precipitate was filtered,washed with ethanol (10 mL), and vacuum dried at 40° C. for 24 h to give141.2 mg (80.7%) of a white, crystalline solid, mp 140-141° C. Thecompound exhibits a Ki of 15 nM; the effect at muscle sites is 10percent; and the effect at ganglia sites is 5 percent. The compoundexhibits neurotransmitter release of 54 percent.

Example 18 Synthesis of Methyl(3-(5-isopropoxy-3-pyridyloxy)propyl)amineMonogalactarate

[0147] 5-Bromo-3-isopropoxypyridine

[0148] Potassium metal (6.59 g, 168.84 mmol) was dissolved in dry2-propanol (60.0 mL) under nitrogen. The resulting potassiumisopropoxide was heated with 3,5-dibromopyridine (20.00 g, 84.42 mmol)and copper powder (1 g, 5% by weight of 3,5-dibromopyridine) at 140° C.(oil bath temperature) in a sealed glass tube for 14 h. The reactionmixture was cooled to ambient temperature and extracted with diethylether (4×200 mL). The combined ether extracts were dried over sodiumsulfate, filtered, and concentrated by rotary evaporation. The crudeproduct obtained was purified by column chromatography over aluminumoxide, eluting with ethyl acetate-hexane (1:9, v/v). Selected fractionswere combined and concentrated by rotary evaporation, producing apale-yellow oil (12.99 g, 71.2%).

[0149] 5-lsopropoxy-3-pyridylamine

[0150] Crude 5-bromo-3-isopropoxypyridine (3.71 g, 17.18 mmol) wasdissolved in methanol (46 mL) and added to concentrated ammoniumhydroxide (29.7%, 14.8 M, 50 mL) and copper(I) bromide (2.46 g, 17.18mmol) in a heavy-walled glass pressure-tube apparatus. The tube wassealed and the mixture was stirred and heated at 170° C. (oil bathtemperature) for 24 h. After cooling, the solution was concentrated byrotary evaporation. Sodium carbonate solution (17.6%, 200 mL) was added,and the mixture was extracted with CH₂Cl₂ (4×50 mL). The combined CH₂Cl₂extracts were dried (MgSO₄), filtered, and concentrated by rotaryevaporation to give 1.88 g (72.0%) of a brown oil.

[0151] 5-lsopropoxypyridin-3-ol

[0152] A mixture of concentrated sulfuric acid (18 M, 2.64 mL), water(3.59 mL) and crushed ice (6.20 g) was added to5-isopropoxy-3-pyridylamine (1.88 g, 12.38 mmol). The cold mixture (0-5°C.) was stirred for 10 min and a solution of sodium nitrite (0.85 g,12.38 mmol) in water (2.5 mL) was then added. After stirring for 10 min,a boiling solution of concentrated sulfuric acid (8.0 mL) and water (6.2mL) was added. The mixture was heated until all solids dissolved. Ice(5.0 g) was added to cool the solution. The pH was adjusted to 8 with10% NaOH solution. Saturated NaCl solution (100 mL) was added, and themixture was extracted with ethyl acetate (4×100 mL). The combined ethylacetate extracts were dried (MgSO₄), filtered and concentrated by rotaryevaporation to give 1.69 g (89.4%) of a brown oil.

[0153] 5-(3-Chloropropoxy)-3-isopropoxypyridine

[0154] Under a nitrogen atmosphere, a solution of5-isopropoxypyridin-3-ol (1.04 g, 6.80 mmol) in DMF (10 mL) was slowlyadded over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride(0.25 g of an 80% dispersion in mineral oil, 8.33 mmol) in DMF (15 mL).The mixture was allowed to warm to ambient temperature and furtherstirred for 1 h. To this slurry was added drop-wise over 5 min,1-chloro-3-iodopropane (1.67 g, 8.16 mmol), and the resulting dark brownmixture was stirred at ambient temperature for 4 h. Cold water (25 mL)was carefully added, followed by saturated NaCl solution (25 mL). Theresulting mixture was extracted with ether (4×50 mL). The combined etherextracts were dried (MgSO₄), filtered, and concentrated by rotaryevaporation producing a dark-brown oil (0.92 g, 59.0%).

[0155] Methyl(3-(5-isopropoxy-3-pyridyloxy)propyl)amine

[0156] Crude 5-(3-chloropropoxy)-3-isopropoxypyridine (0.92 g, 4.01mmol) was dissolved in methanol (10 mL) and added to a 40 wt % aqueoussolution of methylamine (10 mL) in a heavy-walled glass pressure-tubeapparatus. The tube was sealed and the mixture was stirred and heated at100° C. (oil bath temperature) for 4 h. After cooling, the solution wasconcentrated by rotary evaporation. Saturated NaCl solution (50 mL) wasadded, and the mixture was basified with 100% NaOH solution to pH 11.The mixture was extracted with ether (4×50 mL). The combined etherextracts were dried (MgSO₄), filtered and concentrated by rotaryevaporation to give 1.98 g of a brown oil. The product was purified bycolumn chromatography on silica gel (60 g) eluting with hexane to removeimpurities, followed by CHCl₃—CH₃OH-Et₃N (50:50:2, v/v/v) to collect theproduct. Selected fractions containing the product were combined andconcentrated by rotary evaporation. The resulting brown oil wasdissolved in CHCl₃ (25 mL), dried (MgSO₄), filtered, and concentrated byrotary evaporation to give 0.64 g (71.6%) of a brown oil.

[0157] Methyl(3-(5-isopropoxy-3-pyridyloxy)propyl)amine Monogalactarate

[0158] To a solution of methyl(3-(5-isopropoxy-3-pyridyloxy)propyl)amine(0.643 g, 2.87 mmol) in ethanol (10.7 mL) was added galactaric acid(302.0 mg, 1.44 mmol). Water (3.0 mL) was added drop-wise, while warmingthe solution to near reflux. To remove some white, insoluble crystals,the warm solution was filtered through a glass wool plug, washing thefilter plug with a warm solution of ethanol-water (4:1, v/v) (3.4 mL).The filtrate was diluted with ethanol (16 mL), producing a whiteprecipitate. The mixture was allowed to cool to ambient temperature andwas further cooled at 5° C. for 48 h. The precipitate was filtered,washed with ethanol (10 mL), and vacuum dried at 40° C. for 24 h to give251.1 mg (53.2%) of a white, crystalline solid, mp 118-120° C. Thecompound exhibits a Ki of 21 nM; the effect at muscle sites is 22percent; and the effect at ganglia sites is 0 percent. The compoundexhibits neurotransmitter release of 36 percent.

Example 19 Synthesis ofMethyl(3-(5-(phenylmethoxy)(3-pyridyloxy))propyl)amine Hemigalactarate

[0159] 5-Bromo-3-(phenylmethoxy)pyridine

[0160] Under a nitrogen atmosphere, small pieces of sodium (1.48 g, 64.4mmol) were added to benzyl alcohol (17.11 g, 158 mmol), and the mixturewas stirred and heated at 70° C. for 18 h. To the stirring, viscousmixture was added 3,5-dibromopyridine (5.00 g, 21.1 mmol), copper powder(0.255 g, 4.0 mmol) and benzyl alcohol (15 mL). The mixture was furtherheated at 100° C. for 48 h. The reaction mixture was allowed to cool toambient temperature, diluted with water (50 mL), and extracted withethyl ether (5×50 mL). The combined ether layers were dried (Na₂SO₄),filtered, and concentrated. Distillation at 68-72° C. and 2.6 mm Hgremoved excess benzyl alcohol. The remaining yellowish, brown residuewas purified by vacuum distillation at 0.05 mm Hg to yield 3.17 g(38.0%) of a white, crystalline solid, mp 64-66° C.

[0161] 5-(Phenylmethoxy)-3-pyridylamine

[0162] A thick-walled glass pressure tube was charged with copper(II)sulfate pentahydrate (1.96 g, 7.85 mmol),5-bromo-3-(phenylmethoxy)pyridine (4.00 g, 15.15 mmol) and concentratedaqueous ammonia (29.7%, 14.8 M, 37 mL). The tube was sealed and the darkblue suspension was stirred and heated at ˜180° C. (oil bathtemperature) for 24 h. The mixture was allowed to cool to ambienttemperature. After further cooling in an ice-water bath, the mixture wasconcentrated on a rotary evaporator to a small volume (˜20 mL) of adark-blue solution. The solution was diluted with water (40 mL) andsaturated K₂CO₃ solution (40 mL) and extracted with CHCl₃ (4×40 mL). Thecombined, turbid-brown CHCl₃ extracts were washed with saturated NaClsolution (2×100 ml), dried (Na₂SO₄), filtered and concentrated (rotaryevaporator). The resulting dark-brown oil, was briefly dried on thevacuum pump to give a dark-brown solid (2.06 g). The product waspurified by column chromatography on silica gel (100 g) eluting withCHCl₃-MeOH (3:1 ,v/v). Selected fractions, based on TLC (R_(f) 0.65)analysis, were combined and concentrated to give a 1.64 g (54.1%) of atan-brown solid.

[0163] 5-(Phenylmethoxy)pyridin-3-ol

[0164] The 5-(phenylmethoxy)-3-pyridylamine (1.61 g, 8.00 mmol) wasstirred into concentrated sulfuric acid (1.7 mL), water (2.5 mL) and ice(4 g). This mixture was allowed to stir for 10 min until the solutionbecame homogeneous. To this cold, stirring solution was added a solutionof sodium nitrite (552 mg, 8.00 mmol) in water (2 mL). The mixture wasallowed to stir for 10 min. A boiling solution of concentrated sulfuricacid (5 mL) and water (4 mL) was added. The mixture was heated until allsolids dissolved. Ice was added to cool the reaction. The pH wasadjusted to 8 with 10% NaOH solution and saturated NaCl solution wasadded. The product was extracted with ethyl acetate (4× 100 mL). Thecombined ethyl acetate extracts were dried (Na₂SO₄), filtered,concentrated by rotary evaporation and briefly vacuum to give 1.52 g(94.4%).

[0165] 5-(3-Chloropropoxy)-3-(phenyl methoxy)pyridine

[0166] Under a nitrogen atmosphere, a solution of5-(phenylmethoxy)-pyridine-3-ol (1.52 g, 7.56 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to acold (0-5° C.), stirring slurry of sodium hydride (0.238 g of an 80%dispersion in mineral oil, 7.94 mmol) in DMF (15 mL). The mixture wasallowed to stir and warm to ambient temperature over 1 h. Next,1-chloro-3-iodopropane (1.85 g, 9.07 mmol) was added drop-wise over 5min. The resulting dark-brown mixture was stirred at ambient temperaturefor 4 h. Water (25 mL) was added, followed by saturated NaCl solution(25 mL), and the mixture was extracted with ether (4×50 mL). Thecombined ether extracts were dried (Na₂SO₄), filtered, and concentratedby rotary evaporation to a residue that was dried briefly under highvacuum to give an oil.

[0167] Methyl(3-(5-(phenylmethoxy)(3-pyridyloxy))propyl)amine

[0168] The 5-(3-chloropropoxy)-3-(phenylmethoxy)pyridine (1.52 g, 5.49mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueoussolution of methylamine (50 mL) in a heavy-walled glass pressure-tubeapparatus. The tube was sealed and the mixture was stirred and heated at100° C. (oil bath temperature) for 4 h. After cooling, the mixture wasconcentrated by rotary evaporation. Saturated NaCl solution (25 mL) wasadded to the residue. The pH of the solution was adjusted to 6, andimpurities were extracted with ether (3× 15 mL). The aqueous layer wasbasified to pH 10 with 100% NaOH solution and extracted with chloroform(4×15 mL). The combined chloroform extracts were dried (Na₂SO₄),filtered, and concentrated by rotary evaporation to a residue that wasdried briefly under high vacuum to give 1.07 g (71.7%) of an oil.

[0169] Methyl(3-(5-(phenylmethoxy)(3-pyridyloxy))propyl)amineHemigalactarate

[0170] To a solution of methyl(3-(5-(phenylmethoxy)(3-pyridyloxy))propyl)-amine (1.07 g, 3.929 mmol) in ethanol (15mL) was added galactaric acid (0.413 g, 1.964 mmol). Water (1.5 mL) wasadded drop-wise, while warming the solution to reflux. To remove somewhite, insoluble solids, the warm solution was filtered through a glasswool plug, washing the filter plug with a warm solution of ethanol-water(4:1, v/v) (5 mL). The filtrate was diluted with ethanol (23 mL). Themixture was allowed to cool to ambient temperature; however, no solidsprecipitated. The solution was concentrated by rotary evaporation andbriefly dried under high vacuum. The resulting brown solids weredissolved in a mixture of hot 2-propanol (˜15 mL) and water (0.8 mL);the dark-brown solution was allowed to cool to ambient temperature.After 30 min of precipitation, the batch was diluted with 2-propanol (30mL) and stored at 5° C. for 16 h. The resulting solids were filtered,washed with cold 2-propanol (3×5 mL) and vacuum dried at 45° C. to give0.967 g (65.2%) of a beige powder, mp 137-140° C. The compound exhibitsa Ki of 2 nM; the effect at muscle sites is 1 percent; and the effect atganglia sites is 3 percent. The compound exhibits neurotransmitterrelease of 38 percent.

Example 20 Synthesis of Methyl(3-(6-methyl(3-pyridyloxy))propyl)amineHemigalactarate

[0171] 3-Chloro-1-(6-methyl(3-pyridyloxy))propane

[0172] Under a nitrogen atmosphere, a solution of5-hydroxy-2-methylpyridine (2.00 g, 18.3 mmol) in N, N-dimethylformamide(DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.),stirring slurry of sodium hydride (0.825 g of an 80% dispersion inmineral oil, 27.5 mmol) in DMF (15 mL). The mixture was allowed to stirand warm to ambient temperature over 1 h. Next, 1-chloro-3-iodopropane(4.49 g, 22.0 mmol) was added drop-wise over 5 min. The resultingdark-brown mixture was stirred at ambient temperature for 4 h. Water (25mL) was added, followed by saturated NaCl solution (25 mL), and themixture was extracted with ether (4×50 mL). The combined ether extractswere dried (Na₂SO₄), filtered, and concentrated by rotary evaporation toa residue that was dried briefly under high vacuum to give 4.57 g of anoil.

[0173] Methyl(3-(6-methyl(3-pyridyloxy))propyl)amine

[0174] The 3-chloro-1-(6-methyl(3-pyridyloxy))propane (2.78 g, 18.3mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueoussolution of methylamine (50 mL) in a heavy-walled glass pressure-tubeapparatus. The tube was sealed and the mixture was stirred and heated at100° C. (oil bath temperature) for 4 h. After cooling, the mixture wasconcentrated by rotary evaporation. Saturated NaCl solution (25 mL) wasadded to the residue. The pH was adjusted to 1 with 10% HCl solution andimpurities were extracted with chloroform (4×25 mL). The pH of theaqueous phase was raised to 7 with 10% NaOH solution and otherimpurities were extracted with ether (4×30 mL). The aqueous layer wasbasified to pH 11 with 10% NaOH solution and extracted with ether (4×50mL). The combined ether extracts were dried (Na₂SO₄), filtered, andconcentrated by rotary evaporation to a residue that was dried brieflyunder high vacuum to give 1.224 g (45.3%) of an oil.

[0175] Methyl(3-(6-methyl(3-pyridyloxy))propyl)amine Hemigalactarate

[0176] To a solution of methyl(3-(6-methyl(3-pyridyloxy))propyl)amine(1.224 g, 6.80 mmol) in ethanol (15 mL) was added galactaric acid (0.714g, 3.40 mmol). Water (4 mL) was added drop-wise, while warming thesolution to reflux. To remove some white, insoluble solids, the warmsolution was filtered through a glass wool plug, washing the filter plugwith a warm solution of ethanol-water (4:1, v/v). The filtrate wasdiluted with ethanol (20 mL). The mixture was allowed to cool to ambienttemperature and was further cooled at 5° C. for 72 h. The resultingsolids were filtered, washed with cold ethanol, and vacuum dried at 40°C. to give 1.596 g (82.3%) of a white, fluffy crystalline powder, mp152-155° C. The compound exhibits a Ki of 12 nM; and the effect atmuscle sites is 0 percent. The compound exhibits neurotransmitterrelease of 77 percent.

Example 21 Synthesis of Methyl(3-(2-methyl(3-pyridyloxy))propyl)amineHemigalactarate

[0177] 3-Chloro-1-(2-methyl(3-pyridyloxy))propane

[0178] Under a nitrogen atmosphere, a solution of3-hydroxy-2-methylpyridine (2.00 g, 18.3 mmol) in N, N-dimethylformamide(DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.),stirring slurry of sodium hydride (0.576 g of an 80% dispersion inmineral oil, 19.2 mmol) in DMF (40 mL). The mixture was allowed to stirand warm to ambient temperature over 1 h. The slurry was cooled to 0-5°C., and 1-chloro-3-iodopropane (4.49 g, 22.0 mmol) was added drop-wiseover 5 min. The resulting dark-brown mixture was stirred at ambienttemperature for 2 h. Cold water (25 mL) was added, followed by saturatedNaCl solution (25 mL), and the mixture was extracted with ether (4×100mL). The combined ether extracts were dried (Na₂SO₄), filtered, andconcentrated by rotary evaporation to a residue that was dried brieflyunder high vacuum to give 3.25 g (96.2%) of an oil.

[0179] Methyl(3-(2-methyl(3-pyridyloxy))propyl)amine

[0180] The 3-chloro-1-(2-methyl(3-pyridyloxy))propane (2.00 g, 10.8mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueoussolution of methylamine (50 mL) in a heavy-walled glass pressure-tubeapparatus. The tube was sealed and the mixture was stirred and heated at100° C. (oi I bath temperature) for 4 h. After cooling, the mixture wasconcentrated by rotary evaporation. Saturated NaCl solution (25 mL) wasadded to the residue. The pH of the solution was adjusted to 6, and themixture was extracted with ether (3× 25 mL) to remove impurities. Theaqueous layer was basified to pH 10 with 10% NaOH solution and extractedwith chloroform (4×50 mL). The combined chloroform extracts were dried(Na₂SO₄), filtered, and concentrated to give 1.19 g (61.0%) of an oil.

[0181] Methyl(3-(2-methyl(3-pyridyloxy))propyl)amine Hemigalactarate

[0182] To a solution of methyl(3-(2-methyl(3-pyridyloxy))propyl)amine(1.19 g, 6.61 mmol) in ethanol (12 mL) was added galactaric acid (0.696g, 3.30 mmol). Water (3 mL) was added drop-wise, while warming thesolution to reflux. To remove some white, insoluble solids, the warmsolution was filtered through a glass wool plug, washing the filter plugwith a warm solution of ethanol-water (4:1, v/v) (4 mL). The filtratewas diluted with ethanol (30 mL). The mixture was allowed to cool toambient temperature and was further cooled at 5° C. for 48 h. No solidsprecipitated. Consequently, the solution was concentrated to a flakysolid. The solid was slurried in 2-propanol, filtered, washed with2-propanol, and vacuum dried at 40° C. to give 1.37 g (72.8%) of anoff-white, flaky powder, mp 145-148° C. The compound exhibits a Ki of236 nM; the effect at muscle sites is 0 percent; and the effect atganglia sites is 15 percent. The compound exhibits neurotransmitterrelease of 69 percent.

Example 22 Ethyl(3-(3-pyridyloxy)propyl)amine Hemigalactarate

[0183] 3-Chloro-1-(3-pyridyloxy)propane

[0184] Under a nitrogen atmosphere, a solution of 3-hydroxypyridine(35.00 g, 0.368 mmol) in N,N-dimethylformamide (DMF) (150 mL) was slowlyadded drop-wise over 15 min to a cold (0-5° C.), stirring slurry ofsodium hydride (17.64 g of an 80% dispersion in mineral oil, 0.588 mol)in DMF (250 mL). The mixture was allowed to stir and warm to ambienttemperature over 1 h. The gray slurry was cooled to 0-5° C., and1-chloro-3-iodopropane (90.3 g, 0.442 mol) was added drop-wise over 30min. The resulting dark-brown mixture was allowed to stir and warm toambient temperature over 16 h. Water (500 mL) was added and the mixturewas divided into equal parts. Each half was diluted with saturated NaClsolution (200 mL) and extracted with ether (5×200 mL). All etherextracts were combined and concentrated to give 55.1 g (87.3%) of adark-brown oil.

[0185] Ethyl(3-(3-pyridyloxy)propyl)amine

[0186] The 3-chloro-1-(3-pyridyloxy)propane (1.00 g, 5.84 mmol) wasdissolved in methanol (50 mL) and added to a 2.0 M solution ofethylamine in tetrahydrofuran (5 mL) in a heavy-walled glasspressure-tube apparatus. The tube was sealed and the mixture was stirredand heated at 100° C. (oil bath temperature) for 4 h. After cooling, themixture was concentrated by rotary evaporation. Saturated NaCl solution(25 mL) was added to the residue. The pH of the solution was adjusted to6, and impurities were extracted with ether (3× 15 mL). The aqueouslayer was basified to pH 10 with 10% NaOH solution and extracted withchloroform (4×15 mL). The combined chloroform extracts were dried(Na₂SO₄), filtered, and concentrated by rotary evaporation to a residuethat was dried briefly under high vacuum to give 400 mg (38.1%) of anoil.

[0187] Ethyl(3-(3-pyridyloxy)propyl)amine Hemigalactarate

[0188] To a solution of ethyl(3-(3-pyridyloxy)propyl)amine (400 mg, 2.20mmol) in ethanol (11 mL) was added galactaric acid (233 mg, 1.10 mmol).Water (3.5 mL) was added drop-wise, while warming the solution toreflux. To remove some white, insoluble solids, the warm solution wasfiltered through a glass wool plug, washing the filter plug with a warmsolution of ethanol-water (4:1, v/v) (3.5 mL). The filtrate was dilutedwith ethanol (17 mL). The mixture was allowed to cool to ambienttemperature and was further cooled at 5° C. Very few solidsprecipitated. Consequently, the solution was concentrated to a residuethat was vacuum dried. The solids were slurried in 2-propanol, and the2-propanol was evaporated. The resulting solids were slurried inanhydrous ether. The product was filtered, washed with ether, and vacuumdried at 40° C. to give 348 mg (55.0%) of a brown, flaky powder, mp147-150° C. The compound exhibits a Ki of 66 nM; the effect at musclesites is 13 percent; and the effect at ganglia sites is 13 percent. Thecompound exhibits neurotransmitter release of 57 percent.

Example 23 Synthesis of (Methylethyl)(3-(3-pyridyloxy)propyl)amine

[0189] 3-Chloro-1-(3-pyridyloxy)propane

[0190] Under a nitrogen atmosphere, a solution of 3-hydroxypyridine(35.00 g, 0.368 mmol) in N,N-dimethylformamide (DMF) (150 mL) was slowlyadded drop-wise over 15 min to a cold (0-5° C.), stirring slurry ofsodium hydride (17.64 g of an 80% dispersion in mineral oil, 0.588 mol)in DMF (250 mL). The mixture was allowed to stir and warm to ambienttemperature over 1 h. The gray slurry was cooled to 0-5° C., and1-chloro-3-iodopropane (90.3 g, 0.442 mol) was added drop-wise over 30min. The resulting dark-brown mixture was allowed to stir and warm toambient temperature over 16 h. Water (500 mL) was added and the mixturewas divided into equal parts. Each half was diluted with saturated NaClsolution (200 mL) and extracted with ether (5×200 mL). All etherextracts were combined and concentrated to give 55.1 g (87.3%) of adark-brown oil.

[0191] (Methylethyl)(3-(3-pyridyloxy)propyl)amine

[0192] The 3-chloro-1-(3-pyridyloxy)propane (0.80 g, 4.66 mmol) wasdissolved in methanol (25 mL) and added to diisopropylamine (25 mL) in aheavy-walled glass pressure-tube apparatus. The tube was sealed and themixture was stirred and heated at 100° C. (oil bath temperature) for 4h. After cooling, the mixture was concentrated by rotary evaporation.Saturated NaCl solution (10 mL) was added to the residue, and thesolution (pH 6) was extracted with ether (3×25 mL) to remove impurities.The aqueous layer was basified to pH 10 with 10% NaOH solution, and themixture was extracted with chloroform (4×25 mL). The combined chloroformextracts were dried (Na₂SO₄), filtered, and concentrated by rotaryevaporation to a residue that was dried briefly under high vacuum togive 0.531 g (58.6%) of a dark-brown oil. The compound exhibits a Ki of8500 nM. The compound exhibits neurotransmitter release of 16 percent.

Example 24 Synthesis of Benzyl(3-(3-pyridyloxy)propyl)amine

[0193] 3-Chloro-1-(3-pyridyloxy)propane

[0194] Under a nitrogen atmosphere, a solution of 3-hydroxypyridine(35.00 g, 0.368 mmol) in N,N-dimethylformamide (DMF) (150 mL) was slowlyadded drop-wise over 15 min to a cold (0-5° C.), stirring slurry ofsodium hydride (17.64 g of an 80% dispersion in mineral oil, 0.588 mol)in DMF (250 mL). The mixture was allowed to stir and warm to ambienttemperature over 1 h. The gray slurry was cooled to 0-5° C., and1-chloro-3-iodopropane (90.3 g, 0.442 mol) was added drop-wise over 30min. The resulting dark-brown mixture was allowed to stir and warm toambient temperature over 16 h. Water (500 mL) was added and the mixturewas divided into equal parts. Each half was diluted with saturated NaClsolution (200 mL) and extracted with ether (5×200 mL). All etherextracts were combined and concentrated to give 55.1 g (87.3%) of adark-brown oil.

[0195] Benzyl (3-(3-pyridyloxy)propyl)amine

[0196] The 3-chloro-1-(3-pyridyloxy)propane (0.65 g, 3.78 mmol) wasdissolved in methanol (20 mL) and added to a mixture of benzylamine(13.5 mL) in water (20 mL) in a heavy-walled glass pressure-tubeapparatus. The tube was sealed and the mixture was stirred and heated at120° C. (oil bath temperature) for 3 h. After cooling, the mixture wasconcentrated by rotary evaporation, and saturated NaCl solution (25 mL)was added to the residue. The mixture was acidified to pH 1 with 10% HClsolution and extracted with CHCl₃ (2×35 mL) to remove impurities. Theaqueous phase was basified to pH 10 with 10% NaOH solution, and themixture was extracted with chloroform (4×50 mL). The combined chloroformextracts were dried (MgSO₄), filtered, and concentrated by rotaryevaporation to a residue that was dried briefly under high vacuum togive a brown oil. The oil was concentrated by vacuum distillation toremove excess benzylamine (bp 85° C. at 15 mm Hg). The remaining residue(0.483 g) was purified by column chromatography on silica gel (25 g)eluting with CH₃OH—NH₄OH (50:1, v/v). Fractions containing the product(R_(f) 0.39) were combined and concentrated on a rotary evaporator. Theresidue was re-chromatographed on silica gel (10 g). Fractionscontaining the product were combined and concentrated on a rotaryevaporator. The residue was dissolved in CHCL₃ and the CHCL₃ solutionwas dried (MgSO₄), filtered, and concentrated by rotary evaporation to aresidue that was dried briefly under high vacuum to give 20 mg (2.2%) ofa light-brown oil. The compound exhibits a Ki of 3000 nM. The compoundexhibits neurotransmitter release of 29 percent.

Example 25 Synthesis of Cyclopropyl(3-(3-pyridyloxy)propyl)amineHemigalactarate

[0197] 3-Chloro-1-(3-pyridyloxy)propane

[0198] Under a nitrogen atmosphere, a solution of 3-hydroxypyridine(35.00 g, 0.368 mmol) in N,N-dimethylformamide (DMF) (150 mL) was slowlyadded drop-wise over 15 min to a cold (0-5° C.), stirring slurry ofsodium hydride (17.64 g of an 80% dispersion in mineral oil, 0.588 mol)in DMF (250 mL). The mixture was allowed to stir and warm to ambienttemperature over 1 h. The gray slurry was cooled to 0-5° C., and1-chloro-3-iodopropane (90.3 g, 0.442 mol) was added drop-wise over 30min. The resulting dark-brown mixture was allowed to stir and warm toambient temperature over 16 h. Water (500 mL) was added and the mixturewas divided into equal parts. Each half was diluted with saturated NaClsolution (200 mL) and extracted with ether (5×200 mL). All etherextracts were combined and concentrated to give 55.1 g (87.3%) of adark-brown oil.

[0199] Cyclopropyl(3-(3-pyridyloxy)propyl)amine

[0200] An Ace Glass pressure tube (185 mL) was charged with3-chloro-1-(3-pyridyloxy)propane (0.762 g, 4.437 mmol), cyclopropylamine(8.24 g, 194.3 mmol), water (20 mL) and methanol (20 mL). The resultinglight-brown solution was heated at 120° C. (oil bath temperature) for2.5 h and allowed to cool to ambient temperature over 16 h. The solutionwas concentrated by rotary evaporation to an oily residue that wasdiluted with saturated NaCl solution (25 mL). The mixture was acidifiedto pH 1.0 with 10% HCl solution and extracted with CHCl₃ (2×35 mL) toremove impurities. The aqueous phase was basified to pH 6 with 10% NaOHsolution and extracted (4×25 mL) to remove other impurities. The aqueousphase was basified to pH 10 with 10% NaOH solution and extracted withCHCl₃ (4×50 mL). The combined CHCl₃ extracts were dried (Na₂SO₄),filtered, concentrated (rotary evaporator) and briefly dried under highvacuum to give 0.250 g of a brown oil. The oil was purified by columnchromatography on silica gel (20 g) eluting with CHCl₃-CH₃OH (100:2) toremove impurities, followed by CHCl₃-CH₃OH-Et₃N (50:50:2) to remove theproduct. Selected fractions were combined to give 220 mg (25.8%) of abrown semi-solid.

[0201] Cyclopropyl (3-(3-pyridyloxy)propyl)amine Hemigalactarate

[0202] To a solution of cyclopropyl(3-(3-pyridyloxy)propyl)amine (0.239g, 1.244 mmol) in ethanol (4 mL) was added galactaric acid (130.7 mg,622 mmol). Water (1.0 mL) was added drop-wise, while warming thesolution to near reflux. To remove some white, insoluble crystals, thewarm solution was filtered through a glass wool plug, washing the filterplug with a warm solution of ethanol-water (4:1, v/v) (1 mL). Thefiltrate was diluted with ethanol (6 mL), cooled to ambient temperatureand kept at 5° C. for 24 h. Crystallization did not occur. Consequently,the solution was concentrated by rotary evaporation to a brown, glassyresidue. The residue was dissolved in 2-propanol containing a few dropsof water, and the solution was concentrated to a syrup. The syrup wasslurried in a mixture of 2-propanol-diethyl ether, producing a somewhatpowdery solid. The solvents were evaporated on a rotary evaporator, andthe resulting solids were slurried in a mixture of 2-propanol-diethylether. The mixture was stored at 5° C. for 24 h. The solvent wasdecanted; the tan solids were washed with ether (3×5 mL), decanting thewash each time. The tan solids were dried under a stream of nitrogen andunder high vacuum to give 0.246 g (66.5%) of a light-beige powder, mp124-1 30° C. The compound exhibits a Ki of 165 nM; the effect at musclesites is 9 percent; and the effect at ganglia sites is 10 percent. Thecompound exhibits neurotransmitter release of 51 percent.

Example 26 Synthesis of Methyl(1-methyl-3-(3-pyridyloxy)propyl)amineHemigalactarate

[0203] 3-Bromo-1-(3-pyridyloxy)butane

[0204] Under a nitrogen atmosphere, a solution of 3-hydroxypyridine(1.00 g, 10.52 mmol) in N,N-dimethylformamide (DMF) (10 mL) was slowlyadded to a cold (0° C.), stirring slurry of sodium hydride (0.50 g of an60% dispersion in mineral oil, 12.63 mmol) in DMF (5 mL). After stirring30 min, 1,3-dibromobutane (2.50 g, 11.57 mmol) was slowly addeddrop-wise. The resulting mixture was stirred at 0-4° C. for 16 h. Coldwater (10 mL) was added, and the mixture was extracted with ether (3×100mL). The combined ether extracts were dried (Na₂SO₄), filtered andconcentrated by rotary evaporation to give 2.23 g (92.5%) of an oil.

[0205] Methyl(1-methyl-3-(3-pyridyloxy)propyl)amine

[0206] Crude 3-bromo-1-(3-pyridyloxy)butane (2.00 g, 8.69 mmol) from theprevious step was dissolved in methanol (10 mL) and added to a 40 wt %aqueous solution of methylamine (30 mL) in a heavy-walled glasspressure-tube apparatus. The mixture was stirred and heated at 100° C.(oil bath temperature) for 16 h. After cooling, the mixture wasconcentrated by rotary evaporation, and the product was extracted withchloroform (4×50 mL). The combined chloroform extracts were dried(Na₂SO₄), filtered and concentrated by rotary evaporation to give 1.25 gof a pale-yellow oil. Purification by vacuum distillation yielded 0.94 g(60.3%) of a colorless oil, bp 65-67° C. at 0.5 mm Hg.

[0207] Methyl(1-methyl-3-(3-pyridyloxy)propyl)amine Hemigalactarate

[0208] To a solution of methyl(1-methyl-3-(3-pyridyloxy)propyl)amine(0.92 g, 5.11 mmol) in ethanol (25 mL) at 70° C. was added galactaricacid (0.537 g, 2.55 mmol). Water (0.5 mL) was added drop-wise, whilestirring producing a clear solution. Some white, insoluble solids wereremoved by filtration. The filtrate was concentrated to 15 mL, and wasallowed to cool to ambient temperature. After standing for 16 h, theprecipitate was filtered, washed with ether (10 mL) and vacuum dried at45° C. for 18 h to give 1.15 g (78.9%) of an off-white, amorphouspowder, mp 134-136° C. The compound exhibits a Ki of 138 nM; the effectat muscle sites is 16 percent; and the effect at ganglia sites is 20percent. The compound exhibits neurotransmitter release of 49 percent.

Example 27 Synthesis of(3-(5-Chloro(3-pyridyloxy))-1-methylpropyl)methylamine Hemigalactarate

[0209] 3-Bromo-1-(5-chloro(3-pyridyloxy)butane

[0210] Under a nitrogen atmosphere, a solution of5-chloro-3-hydroxypyridine (1.00 g, 7.72 mmol) in N,N-dimethylformamide(DMF) (10 mL) was slowly added to a cold (0° C.), stirring slurry ofsodium hydride (0.40 g of an 60% dispersion in mineral oil, 11.58 mmol)in DMF (5 mL). After stirring 30 min, 1,3-dibromobutane (1.83 g, 8.49mmol) was added drop-wise. The resulting mixture was stirred at 0° C.for 14 h. Cold water (10 mL) was added, and the mixture was extractedwith ether (3×100 mL). The combined ether extracts were dried (Na₂SO₄),filtered and concentrated by rotary evaporation to give 1.80 g (88.50%)of pale-yellow oil.

[0211] (3-(5-Chloro(3-pyridyloxy))-1-methylpropyl)methylamine

[0212] Crude 3-bromo-1-(5-chloro(3-pyridyloxy)butane (1.50 g, 5.67 mmol)from the previous step was dissolved in methanol (10 mL) and added to a40 wt % aqueous solution of methylamine (40 mL) in a heavy-walled glasspressure-tube apparatus. The mixture was stirred and heated at 100° C.(oil bath temperature) for 14 h. After cooling, the mixture wasconcentrated by rotary evaporation, and the product was extracted withchloroform (3×100 mL). The combined chloroform extracts were dried(Na₂SO₄), filtered, and concentrated by rotary evaporation to give apale-brown oil. The product was dissolved in cold, 15% aqueous HCl (15mL), stirred at 0° C. for 45 min and extracted with chloroform (50 mL).The aqueous layer was cooled to 0° C., basified with 15% aqueous NaOHsolution to pH 8-9 and extracted with chloroform (3×75 mL). The combinedextracts were dried (Na₂SO₄), filtered and concentrated by rotaryevaporation to give 0.929 g (76.6%) of a pale-yellow oil.

[0213] (3-(5-Chloro(3-pyridyloxy))-1-methylpropyl)methylamineHemigalactarate

[0214] To a solution of(3-(5-chloro(3-pyridyloxy))-1-methylpropyl)-methylamine (0.70 g, 3.27mmol) in ethanol (20 mL) at 70° C. was added galactaric acid (0.343 g,1.63 mmol). Water (0.5 mL) was added drop-wise while stirring, producinga clear solution. Some white, insoluble solids were removed byfiltration. The filtrate was concentrated to 10 mL and was allowed tocool to ambient temperature. After standing 16 h, the precipitate wasfiltered, washed with ether (10 mL) and vacuum dried at 45° C. for 24 hto give 0.775 g (74.3%) of a light-beige, amorphous powder, mp 155-157°C. The compound exhibits a Ki of 1601 nM. The compound exhibitsneurotransmitter release of 30 percent.

Example 28 Synthesis of Methyl(3-(3-nitrophenoxy)propyl)amineHemigalactarate

[0215] 1-(3-Chloropropoxy)-3-nitrobenzene

[0216] Under a nitrogen atmosphere, a solution of 3-nitrophenol (15.00g, 108.0 mmol) in N, N-dimethylformamide (DMF) (10 mL) was addeddrop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodiumhydride (3.42 g of an 80% dispersion in mineral oil, 114.0 mmol) in DMF(40 mL). The mixture was allowed to stir and warm to ambient temperatureover 1 h. The mixture was cooled to 0-5° C., and 1-chloro-3-iodopropane(26.37 g, 127.0 mmol) was added drop-wise over 5 min. The resultingdark-brown mixture was stirred at ambient temperature for 2 h. Water (25mL) was added, followed by saturated NaCl solution (25 mL), and themixture was extracted with ether (4×50 mL). The combined ether extractswere dried (Na₂SO₄), filtered, and concentrated by rotary evaporation toa residue that was dried briefly under high vacuum to give 19.75 g(85.1%) of an oil.

[0217] Methyl(3-(3-nitrophenoxy)propyl)amine

[0218] The 1-(3-chloropropoxy)-3-nitrobenzene (1.00 g, 4.65 mmol) wasdissolved in methanol (25 mL) and added to a 40 wt % aqueous solution ofmethylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. Thetube was sealed and the mixture was stirred and heated at 100° C. (oilbath temperature) for 4 h. After cooling, the mixture was concentratedby rotary evaporation. Saturated NaCl solution (25 mL) was added to theresidue. The pH of the solution was adjusted to 6, and impurities wereextracted with ether (3× 15 mL). The aqueous layer was basified to pH 10with 10% NaOH solution and extracted with chloroform (4×15 mL). Thecombined chloroform extracts were dried (Na₂SO₄), filtered, andconcentrated by rotary evaporation to a residue that was dried brieflyunder high vacuum to give 493 mg (50.6%) of an oil.

[0219] Methyl(3-(3-nitronhenoxy)propyl)amine Hemigalactarate

[0220] To a solution of methyl(3-(3-nitrophenoxy)propyl)amine (493 mg,2.35 mmol) in ethanol (10 mL) was added galactaric acid (247 mg, 1.17mmol). Water (3.0 mL) was added drop-wise, while warming the solution tonear reflux. To remove some white, insoluble crystals, the warm solutionwas filtered through a glass wool plug, washing the filter plug with awarm solution of ethanol-water (4:1, v/v). The filtrate was diluted withethanol (15 mL), producing a white precipitate. The mixture was allowedto cool to ambient temperature and was further cooled at 5° C. Theprecipitate was filtered, washed with ethanol (10 mL), and vacuum driedat 40° C. for 24 h to give 617 mg (83.5%) of white, fluffy, crystals, mp186-187° C. The compound exhibits a Ki of 392 nM; the effect at musclesites is 10 percent; and the effect at ganglia sites is 9 percent. Thecompound exhibits neurotransmitter release of 67 percent.

Example 29 Synthesis of 1-(3-Chloropropoxy)-3-nitrobenzeneHemigalactarate 1-(3-Chloropropoxy)-3-nitrobenzene

[0221] Under a nitrogen atmosphere, a solution of 3-nitrophenol (15.00g, 108.0 mmol) in N, N-dimethylformamide (DMF) (10 mL) was addeddrop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodiumhydride (3.42 g of an 80% dispersion in mineral oil, 114.0 mmol) in DMF(40 mL). The mixture was allowed to stir and warm to ambient temperatureover 1 h. The mixture was cooled to 0-5° C., and 1-chloro-3-iodopropane(26.37 g, 127.0 mmol) was added drop-wise over 5 min. The resultingdark-brown mixture was stirred at ambient temperature for 2 h. Water (25mL) was added, followed by saturated NaCl solution (25 mL), and themixture was extracted with ether (4×50 mL). The combined ether extractswere dried (Na₂SO₄), filtered, and concentrated by rotary evaporation toa residue that was dried briefly under high vacuum to give 19.75 g(85.1%) of an oil.

[0222] 3-(3-Chloropropoxy)phenylamine

[0223] Under a nitrogen atmosphere, a solution of1-(3-chloropropoxy)-3-nitrobenzene (7.90 g, 36.64 mmol) in ethanol wasadded to 10% palladium on carbon in a Parr hydrogenation bottle. Themixture was hydrogenated on a Parr shaker. Because of very littlehydrogen uptake, Raney® nickel (50% slurry in water) was carefully addedto the reaction mixture and hydrogenation continued. When hydrogenationwas complete the mixture was filtered through a mat of Celite® filteraid. The filtrate was concentrated on a rotary evaporator to an oil.

[0224] 3-(3-Aminopropoxy)phenylamine

[0225] The 3-(3-chloropropoxy)phenylamine (1.98 g, 11.6 mmol) wasdissolved in methanol (25 mL) and added to concentrated ammoniumhydroxide solution (29.7%, 14.8 M, 50 mL) in a heavy-walled glasspressure-tube apparatus. The tube was sealed and the mixture was stirredand heated at 100° C. (oil bath temperature) for 6 h. After cooling, themixture was concentrated by rotary evaporation. Saturated NaCl solution(10 mL) was added to the residue, and the solution (pH 6) was extractedwith ether (3×25 mL) to remove impurities. The aqueous layer wasbasified to pH 10 with 10% NaOH solution, and the mixture was extractedwith chloroform (4×25 mL). The combined chloroform extracts were dried(Na₂SO₄), filtered, and concentrated by rotary evaporation to a residuethat was dried briefly under high vacuum to give 1.37 g of an oil.

[0226] 3-(3-Aminopropoxy)phenylamine Hemigalactarate

[0227] To a solution of 3-(3-aminopropoxy)phenylamine (1.37 g, 8.25mmol) in ethanol (12 mL) was added galactaric acid (0.867 g, 4.13 mmol).Water (3 mL) was added drop-wise, while warming the solution to reflux.To remove some white, insoluble solids, the warm solution was filteredthrough a glass wool plug, washing the filter plug with a warm solutionof ethanol-water (4:1, v/v) (4 mL). The filtrate was diluted withethanol (80 mL). The mixture was allowed to cool to ambient temperatureand was further cooled at 5° C. No solids had formed. Consequently, thesolution was concentrated to a residue that was vacuum dried. The solidswere slurried in hot 2-propanol and cooled to ambient temperature. Theproduct was filtered, washed with 2-propanol and vacuum dried at 40° C.to give 1.462 g (65.4%) of a beige, crystalline powder, mp 182-185° C.The compound exhibits a Ki of 442 nM. The compound exhibitsneurotransmitter release of 14 percent.

Example 30 Synthesis of (3-(3-Aminophenoxy)propyl)methylamineHemigalactarate

[0228] 1-(3-Chloropropoxy)-3-nitrobenzene

[0229] Under a nitrogen atmosphere, a solution of 3-nitrophenol (15.00g, 108.0 mmol) in N, N-dimethylformamide (DMF) (10 mL) was addeddrop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodiumhydride (3.42 g of an 80% dispersion in mineral oil, 114.0 mmol) in DMF(40 mL). The mixture was allowed to stir and warm to ambient temperatureover 1 h. The mixture was cooled to 0-5° C., and 1-chloro-3-iodopropane(26.37 g, 127.0 mmol) was added drop-wise over 5 min. The resultingdark-brown mixture was stirred at ambient temperature for 2 h. Water (25mL) was added, followed by saturated NaCl solution (25 mL), and themixture was extracted with ether (4×50 mL). The combined ether extractswere dried (Na₂SO₄), filtered, and concentrated by rotary evaporation toa residue that was dried briefly under high vacuum to give 19.75 g(85.1%) of an oil.

[0230] 3-(3-Chloropropoxy)phenylamine

[0231] Under a nitrogen atmosphere, a solution of1-(3-chloropropoxy)-3-nitrobenzene (7.90 g, 36.64 mmol) in ethanol wasadded to 10% palladium on carbon in a Parr hydrogenation bottle. Themixture was hydrogenated on a Parr shaker. Because of very littlehydrogen uptake, Raney® nickel (50% slurry in water) was carefully addedto the reaction mixture and hydrogenation continued. When hydrogenationwas complete the mixture was filtered through a mat of Celite® filteraid. The filtrate was concentrated on a rotary evaporator to an oil.

[0232] (3-(3-Aminophenoxy)propyl)methylamine

[0233] The 3-(3-chloropropoxy)phenylamine was dissolved in methanol (25mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in aheavy-walled glass pressure-tube apparatus. The tube was sealed and themixture was stirred and heated at 100° C. (oil bath temperature) for 4h. After cooling, the mixture was concentrated by rotary evaporation.Saturated NaCl solution (25 mL) was added to the residue. The pH of thesolution was adjusted to 6, and impurities were extracted with ether(4×30 mL). The aqueous layer was basified to pH 11 with 10% NaOHsolution and extracted with chloroform (4× 50 mL). The combinedchloroform extracts were dried (Na₂SO₄), filtered, and concentrated byrotary evaporation to a residue that was dried briefly under high vacuumto give 2.77 g of an oil.

[0234] (3-(3-Aminophenoxy)propyl)methylamine Hemigalactarate

[0235] To a solution of (3-(3-aminophenoxy)propyl)methylamine (2.77 g,15.30 mmol) in ethanol was added galactaric acid (1.61 g, 7.65 mmol).Water was added drop-wise, while warming the solution to reflux. Toremove some white, insoluble solids, the warm solution was filteredthrough a glass wool plug, washing the filter plug with a warm solutionof ethanol-water (4:1, v/v). The filtrate was diluted with ethanol. Themixture was allowed to cool to ambient temperature and was furthercooled at 5° C. No solids had formed. Consequently, the solution wasconcentrated to a residue that was vacuum dried. The solids wereslurried in 2-propanol, and the 2-propanol was evaporated. The resultingsolids were slurried in anhydrous ether. The product was filtered,washed with ether and vacuum dried at 40° C. to give 3.928 g (89.6%) ofbrown, powdery crystals, mp 160-170° C. The compound exhibits a Ki of 64nM; the effect at muscle sites is 11 percent; and the effect at gangliasites is 5 percent. The compound exhibits neurotransmitter release of 30percent. The compound exhibits neurotransmitter release of 60 percent.

Example 31 Synthesis of Dimethyl(3-(3-(methylamino)propoxy)phenyl)amineHemigalactarate

[0236] (3-(3-Chloropropoxy)phenyl)dimethylamine

[0237] Under a nitrogen atmosphere, a solution of3-(dimethylamino)phenol (3.50 g, 25.51 mmol) in DMF (30 mL) was slowlyadded over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride(0.80 g of an 80% dispersion in mineral oil, 26.79 mmol) in DMF (40 mL).The mixture was allowed to warm to ambient temperature and furtherstirred for 1.25 h. The resulting brown mixture was cooled to 0-5° C. Tothis slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (6.26g, 30.62 mmol). The resulting reddish brown mixture was stirred atambient temperature for 4.25 h. Cold water (35 mL) was carefully added,followed by saturated NaCl solution (35 mL). The resulting mixture wasextracted with ether (4×50 mL). The combined dull-yellow ether extractswere dried (Na₂SO₄), filtered, and concentrated by rotary evaporationproducing a light-brown oil (5.65 g).

[0238] Dimethyl(3-(3-(methylamino)propoxy)phenyl)amine

[0239] The crude (3-(3-chloropropoxy)phenyl)dimethylamine (4.06 g, 19.01mmol) was dissolved in methanol (30 mL) and added to a 40 wt % aqueoussolution of methylamine (75 mL) in a heavy-walled glass pressure-tubeapparatus. The tube was sealed and the mixture was stirred at ambienttemperature for 16 h, followed by heating at 87° C. (oil bathtemperature) for 3 h. After cooling, the solution was concentrated byrotary evaporation to a lavender-brown semi-solid. Saturated NaClsolution (35 mL) was added. The mixture was acidified to pH 1 with 10%HCl solution and extracted with CHCl₃ (5×30 mL) to remove impurities.The dark-brown aqueous layer was basified to pH 7 with 30% NaOH solutionand extracted with ether (4×40 mL) to remove impurities. The brownaqueous layer was basified with 30% NaOH solution to pH 12 and extractedwith ether (4×50 mL). The combined ether extracts were dried (Na₂SO₄),filtered and concentrated by rotary evaporation, producing an oil. Theproduct was dried briefly under high vacuum to afford 2.24 g (56.6%) ofa dark-brown oil.

[0240] Dimethyl(3-(3-(methylamino)propoxy)phenyl)amine Hemigalactarate

[0241] To a solution of dimethyl(3-(3-(methylamino)propoxy)phenyl)amine(2.23 g, 10.71 mmol) in ethanol (34 mL) was added galactaric acid (1.13g, 5.35 mmol). Water (4.8 mL) was added drop-wise, while warming thesolution to near reflux. To remove some white, insoluble crystals, thewarm solution was filtered through a glass wool plug, washing the filterplug with a warm solution of ethanol-water (4:1, v/v) (10 mL). Thefiltrate was diluted with ethanol (50 mL), producing a precipitate. Themixture was allowed to cool to ambient temperature and was furthercooled at 5° C. for 16 h. The precipitate was filtered, washed withethanol (3×10 mL) and vacuum dried at 40° C. for 48 h to give 2.95 g(87.9%) of a fluffy, light-gray to off-white powder, mp 159.5-162.5° C.(d). The compound exhibits a Ki of 10000 nM. The compound exhibitsneurotransmitter release of 16 percent.

Example 32 Synthesis ofMethyl(3-tricyclo[7.3.1.0<5,13>]tridec-2-yloxypropyl)amineHemigalactarate

[0242] 3-Chloro-1-tricyclo[7.3.1.0<5,13>tridec-2-yloxypropane

[0243] Under a nitrogen atmosphere, a solution of 8-hydroxyjulolidine(tetrahydro-1H,5H-benzo[ij]quinolizin-8-ol) (2.00 g, 10.57 mmol) in DMF(15 mL) was slowly added over 5 min to a cold (0-5° C.), stirring slurryof sodium hydride (0.38 g of an 80% dispersion in mineral oil, 12.67mmol) in DMF (15 mL). The mixture was allowed to warm to ambienttemperature and further stirred for 1 h. To this slurry was addeddrop-wise over 5 min, 1-chloro-3-iodopropane (2.59 g, 12.67 mmol), andthe resulting brown mixture was stirred at ambient temperature for 4 h.Cold water (25 mL) was carefully added, followed by saturated NaClsolution (25 mL). The resulting mixture was extracted with ether (4×50mL). The combined ether extracts were dried (MgSO₄), filtered,concentrated by rotary evaporation to a residue that was dried brieflyunder high vacuum producing 1.90 g (67.6%) of an oil.

[0244] Methyl(3-tricyclo[7.3.1.0<5,13>]tridec-2-yloxypropyl)amine

[0245] Crude 3-chloro-1-tricyclo[7.3.1.0<5,13>tridec-2-yloxypropane(1.90 g, 7.15 mmol) was dissolved in methanol (25 mL) and added to a 40wt % aqueous solution of methylamine (20 mL) in a heavy-walled glasspressure-tube apparatus. The tube was sealed and the mixture was stirredand heated at 100° C. (oil bath temperature) for 4 h. After cooling, thesolution was concentrated by rotary evaporation, and saturated NaClsolution (50 mL) was added. The mixture was extracted with ether (4×50mL). The combined ether extracts were dried (MgSO₄), filtered andconcentrated by rotary evaporation to give a residue (2.60 g). Theresidue was purified by column chromatography on silica gel (60 g)eluting with CHCl₃-CH₃OH (1:1, v/v) to remove impurities, followed byCHCl₃-CH₃OH-Et₃N (50:50:2, v/v/v) to collect the product. Selectedfractions containing the product were combined and concentrated byrotary evaporation to afford 1.694 g (91.0%) of material.

[0246] Methyl(3-tricyclo[7.3.1.0<5,13>]tridec-2-yloxypropyl)amineHemigalactarate

[0247] To a solution ofmethyl(3-tricyclo[7.3.1.0<5,13>]tridec-2-yloxypropyl)amine (1.694 g,6.51 mmol) in ethanol (23 mL) was added galactaric acid (0.656 g, 3.12mmol). Water (6.6 mL) was added drop-wise, while warming the solution tonear reflux. Upon cooling the mixture to ambient temperature, theresulting precipitate was filtered. The solids were collected anddissolved in a mixture of methanol (50 mL) and water (75 mL), whilewarming the solution to near reflux. The warm solution was filtered toremove a few insoluble solids and cooled. However, crystallization didnot occur. The solution was concentrated, and the resulting solids wererecrystallized from ethanol-water. After cooling at 5° C. for 48 h, theprecipitate was filtered, washed with ethanol and vacuum dried at 40° C.for 16 h to give 0.699 g (29.4%) of a yellow, crystalline solid, mp169-171° C. The compound exhibits a Ki of 100000 nM.

Example 33 Synthesis of (3-(3-Methoxyphenoxy)propyl)methylamine

[0248] 3-Chloro-1-(3-methoxyphenoxy)propane

[0249] Under a nitrogen atmosphere, a solution of 3-methoxyphenol (2.00g, 16.11 mmol) in DMF (10 mL) was slowly added over 5 min to a cold(0-5° C.), stirring slurry of sodium hydride (0.70 g of an 80%dispersion in mineral oil, 23.33 mmol) in DMF (15 mL). The mixture wasallowed to warm to ambient temperature and further stirred for 1 h. Tothis slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (3.95g, 19.32 mmol), and the resulting brown mixture was stirred at ambienttemperature for 4 h. Cold water (25 mL) was carefully added, followed bysaturated NaCl solution (25 mL). The resulting mixture was extractedwith ether (4×50 mL). The combined ether extracts were dried (MgSO₄),filtered, concentrated by rotary evaporation to a residue that was driedbriefly under high vacuum producing a light-brown oil (3.27 g,quantitative yield).

[0250] (3-(3-Methoxyphenoxy)propyl)methylamine

[0251] Crude 3-chloro-1-(3-methoxyphenoxy)propane (1.27 g, 6.33 mmol)was dissolved in methanol (25 mL) and added to a 40 wt % aqueoussolution of methylamine (25 mL) in a heavy-walled glass pressure-tubeapparatus. The tube was sealed and the mixture was stirred and heated at100° C. (oil bath temperature) for 4 h. After cooling, the solution wasconcentrated by rotary evaporation, and saturated NaCl solution (50 mL)was added. The mixture was acidified to pH 1 with 10% HCl solution, andextracted with CHCl₃ (4×25 mL) to remove impurities. The pH of theaqueous phase was adjusted to 7 with 10% NaOH solution, and the mixturewas extracted with ether (4×30 mL) to remove impurities. The aqueousphase was basified with 100% NaOH solution to pH 11. The mixture wasextracted with ether (4×50 mL). The combined ether extracts were dried(MgSO₄), filtered and concentrated by rotary evaporation to give aresidue. The residue was briefly dried under high vacuum producing alight-brown oil (0.11 g). The oil was purified by column chromatographyon silica gel (10 g) eluting with CHCl₃-CH₃OH (1:1, v/v) to removeimpurities, followed by CHCl₃-CH₃OH-Et₃N (50:50:2, v/v/v) to collect theproduct (R_(f) 0.27). Selected fractions containing the product werecombined and concentrated by rotary evaporation. The resulting brown oilwas dissolved in CHCl₃, and the CHCl₃ solution was dried (MgSO₄),filtered and concentrated by rotary evaporation to a residue. Theresidue was dried briefly under vacuum to give 0.021 g (1.7%) of alight-brown oil. The compound exhibits a Ki of 5300 nM.

Example 34 Synthesis of(3-Benzol[3,4-d]1,3-dioxolan-5-yloxypropyl)methylamine Hemigalactarate

[0252] 1-Benzol[3,4-d]1,3-dioxolan-5-yloxy-3-chloropropane

[0253] Under a nitrogen atmosphere, a solution of sesamol (2.00 g, 14.48mmol) in DMF (15 mL) was slowly added over 5 min to a cold (0-5° C.),stirring slurry of sodium hydride (0.65 g of an 80% dispersion inmineral oil, 21.67 mmol) in DMF (10 mL). The mixture was allowed to warmto ambient temperature and further stirred for 1 h. To this slurry wasadded drop-wise over 5 min, 1-chloro-3-iodopropane (3.55 g, 17.37 mmol),and the resulting brown mixture was stirred at ambient temperature for 4h. Cold water (25 mL) was carefully added, followed by saturated NaClsolution (25 mL). The resulting mixture was extracted with ether (4×50mL). The combined ether extracts were dried (MgSO₄), filtered,concentrated by rotary evaporation to a residue that was dried brieflyunder high vacuum producing a brown oil.

[0254] (3-Benzo[3,4-d]1,3-dioxolan-5-yloxypropyl)methylamine

[0255] Crude 1-benzo[3,4-d]1,3-dioxolan-5-yloxy-3-chloropropane (1.95 g,9.1 mmol) was dissolved in methanol (25 mL) and added to a 40 wt %aqueous solution of methylamine (25 mL) in a heavy-walled glasspressure-tube apparatus. The tube was sealed and the mixture was stirredand heated at 100° C. (oil bath temperature) for 4 h. After cooling, thesolution was concentrated by rotary evaporation, and saturated NaClsolution (50 mL) was added. The mixture was acidified to pH 1 with 10%HCl solution, and extracted with CHCl₃ (4×25 mL) to remove impurities.The pH of the aqueous phase was adjusted to 7 with 10% NaOH solution,and the mixture was extracted with ether (4×30 mL) to remove impurities.The aqueous phase was basified with 10% NaOH solution to pH 11. Themixture was extracted with ether (4×50 mL). The combined ether extractswere dried (MgSO₄), filtered and concentrated by rotary evaporation togive a residue. The residue was briefly dried under high vacuumproducing a light-brown oil (0.286 g). The oil was purified by columnchromatography on silica gel (20 g) eluting with CHCl₃-CH₃OH (1:1, v/v)to remove impurities, followed by CHCl₃-CH₃OH-Et₃N (50:50:2, v/v/v) tocollect the product (R_(f) 0.14). Selected fractions containing theproduct were combined and concentrated by rotary evaporation. Theresulting brown oil was dissolved in CHCl₃ and the CHCl₃ solution wasdried (MgSO₄), filtered and concentrated by rotary evaporation to aresidue. The residue was dried under vacuum at 40° C. to give 0.274 g(14.4%) of a brown oil.

[0256] (3-Benzo[3,4-d]1,3-dioxolan-5-yloxypropyl)methylamineHemigalactarate

[0257] To a solution of(3-benzo[3,4-d]1,3-dioxolan-5-yloxypropyl)methylamine (0.252 g, 1.21mmol) in ethanol (6 mL) was added galactaric acid (140.0 mg, 0.67 mmol).Water (1.5 mL) was added drop-wise, while warming the solution to nearreflux. To remove some white, insoluble crystals, the warm solution wasfiltered through a glass wool plug, washing the filter plug with a warmsolution of ethanol-water (4:1, v/v) (1.5 mL). The filtrate was dilutedwith ethanol (7.5 mL). The mixture was allowed to cool to ambienttemperature and was further cooled at 5° C. for 48 h. The precipitatewas filtered, washed with ether, and vacuum dried at 40° C. for 16 h togive 301 mg (79.4%) of a white, crystalline solid, mp 158-160° C. Thecompound exhibits a Ki of 16600 nM. The compound exhibitsneurotransmitter release of 41 percent.

Example 35 Synthesis of 3-(4-Piperidinyloxy)pyridine Dihydrochloride

[0258] N-(tert-Butoxycarbonyl)-piperidin-4-one

[0259] This compound was prepared as light-yellow, crystalline plates,mp 71-73.5° C. (literature mp 74-75°) using the general procedure of P.Houghton and G. R. Humphrey, European Patent Application No. 0470668 A1(Merck Sharp and Dohme, Inc.).

[0260] N-(tert-Butoxycarbonyl)-piperidin-4-ol

[0261] A mixture of N-(tert-butoxycarbonyl)-piperidin-4-one (4.90 g,24.59 mmol), sodium borohydride (1.52 g, 40.18 mmol) and methanol wasstirred for 10 h. The solvent was removed by rotary evaporation. Theresidue was treated with portions of acetone (4×20 mL) and evaporatedeach time on a rotary evaporator. Water (10 mL) was added and theproduct was extracted with CHCl₃ (4×20 mL). The combined CHCl₃ extractswere dried (K₂CO₃), filtered and concentrated to afford 3.80 g (76.8%)of a thick syrup, that solidified upon standing.

[0262] 3-(N-(tert-Butoxycarbonyl)-4-piperidinyloxy)pyridine

[0263] Under a nitrogen atmosphere, a cold (0-5° C.), stirring solutionof N-(tert-butoxycarbonyl)-piperidin-4-ol (800 mg, 3.98 mmol),3-hydroxypyridine (378 mg, 3.98 mmol) and triphenylphosphine (1.148 g,4.38 mmol) in dry tetrahydrofuran (20 mL) was treated drop-wise viasyringe with diethyl azodicarboxylate (0.75 mL, 830 mg, 4.76 mmol). Themixture was allowed to stir and warm to ambient temperature over 16 h.The solvent was removed by rotary evaporation, and the crude product waspurified by column chromatography over silica gel, eluting withhexane-ethyl acetate (9:1, v/v). Selected fractions were collected andconcentrated to produce 800 mg (72.2%) of a thick syrup.

[0264] 3-(4-Piperidinyloxylpyridine

[0265] A cold (0-5° C.), stirring solution of3-(N-(tert-butoxycarbonyl)-4-piperidinyloxy)pyridine (500 mg, 1.796mmol) in anisole (8 mL) was treated with trifluoroacetic acid (8 mL,11.84 g, 103.8 mmol). The resulting solution was stirred for 30 min. Thevolatiles were removed on a rotary evaporator, and the residue wasneutralized and basified to pH 9 with solid K₂CO₃ and water. The mixturewas extracted with chloroform (4×20 mL). The combined chloroformextracts were dried (K₂CO₃), filtered and concentrated. The crudeproduct was purified by column chromatography over silica gel, elutingwith chloroform-acetone (9:1, v/v). Selected fractions were collectedand concentrated to give 260 mg (81.2%) of an off-white, viscous liquid.

[0266] 3-(4-Piperidinyloxy)pyridine Dihydrochloride

[0267] Concentrated HCl (2 mL) was added to 3-(4-piperidinyloxy)pyridine(260 mg, 1.459 mmol), and the resulting solution was concentrated byrotary evaporation. Ethanol was added to the residue and removed byrotary evaporation to dry the product. The procedure was repeatedseveral times until a solid was obtained. The resulting material wasrecrystallized from 2-propanol. The solids were filtered and dried undervacuum to afford 233 mg (63.7%) of an off-white solid, mp 152-155° C.The compound exhibits a Ki of 592 nM; the effect at muscle sites is 16percent; and the effect at ganglia sites is 9 percent.

Example 36 Synthesis of 3-((3S)-3-Pyrrolidinyloxy)pyridineDihydrochloride

[0268] (3R)-N-(tert-Butoxycarbonyl)-3-hydroxypyrrolidine

[0269] Under a nitrogen atmosphere, di-tert-butyl dicarbonate (12.53 g,57.39 mmol) was slowly added in portions to a cold (0-5° C.), stirringsolution of (R)-(+)-3-pyrrolidinol (5.00 g, 57.39 mmol) intetrahydrofuran (30 mL). The light yellow solution was allowed to stirand warm to ambient temperature over several hours. The solution wasconcentrated (rotary evaporation and high vacuum) to give a yellow oil.The oil was treated with saturated NaHCO₃ solution (100 mL) andextracted with EtOAc (3×75 mL). The combined EtOAc extracts were dried(Na₂SO₄), filtered, concentrated by rotary evaporation and vacuum driedto give a yellow oil containing colorless crystals. The product wasrecrystallized from EtOAc-cyclohexane (˜1:1-1:2). The mixture was cooledat 5° C. for 16 h. The off-white crystals were filtered, washed withcyclohexane (2×5 mL) and vacuum dried at 40° C. for 16 h affording 7.36g (68.5%) of off-white, slightly yellow crystals, mp 62.5-65.5° C.,literature mp 62-65° C. (P. G. Houghton et al., J. Chem. Soc. PerkinTrans 1 (Issue 13): 1421-1424 (1993), [α]^(20.5)D−25.0° (c 1.0, CH₂Cl₂),literature [α]D−22.7° (c 1.0, CH₂Cl₂). The crystallization liquors wereconcentrated, and the syrup was cooled at 5° C. The resulting yellowcrystals were filtered, washed with cyclohexane and vacuum dried at 40°C. producing an additional 2.98 g of a yellow powder, mp 60.5-62.5° C.bringing the total yield to 10.34 g (96.2%).

[0270] 3-((3S)-N-(tert-Butoxycarbonyl)-3-pyrrolidinyloxy)pyridine

[0271] Under a nitrogen atmosphere, diethyl azodicarboxylate (4.65 g,26.70 mmol) was added to a cold (0-5° C.), stirring solution oftriphenylphosphine (7.00 g, 26.70 mmol) in dry tetrahydrofuran (60 mL,distilled from sodium and benzophenone). The mixture was stirred at 0-5°C. for 15 min. The resulting yellow solution was treated drop-wise at0-5° C. with a solution of(3R)-N-(tert-butoxycarbonyl)-3-hydroxypyrrolidine (2.50 g, 13.35 mmol)in dry THF (20 mL) producing a thick yellow mixture. At 0-5° C.,3-hydroxypyridine (2.54 g, 26.70 mmol) was added in one portion. Theresulting yellow solution was allowed to stir and warm to ambienttemperature over 24 h. The solution was diluted with CH₂Cl₂ (150 mL) andwashed with saturated K₂CO₃ solution (2×100 mL). The combined CH₂Cl₂extracts were dried (Na₂SO₄), filtered, concentrated by rotaryevaporation and briefly dried under high vacuum to give a viscous,light-yellow gel. The crude product was purified by columnchromatography on silica gel (302 g), eluting with CHCl₃-CH₃OH (95:5,v/v). Selected fractions containing the product (R_(f) 0.44) werecombined and concentrated to afford 2.50 g of a light-yellow oil, thatcontained solids. Impure fractions were combined and concentrated togive 16 g of solids. The solids were triturated with pentane (4× 75 mL)in an ultrasonic bath, and the pentane filtrate was concentrated to give3.40 g of an oil. The oil was chromatographed on siica gel (180 g),eluting with CHCl₃-acetone (4:1, v/v). Selected fractions containing theproduct (R_(f) 0.29) were combined and concentrated to afford 1.23 g ofa light-yellow oil. The 2.50 g lot was triturated with pentane (2×50 mL)in an ultrasonic bath and the pentane filtrate was concentrated. Theresulting oil was purified by column chromatography on silica gel (50g), eluting with CHCl₃-acetone (4:1, v/v). Selected fractions containingthe product were combined and concentrated to give 0.58 g of alight-yellow oil. Impure fractions from the latter column were combinedand concentrated, and the residue was chromatographed on silica gel (50g) to give 0.28 g of a light-yellow oil. All purified materials werecombined, concentrated and dried under high vacuum to yield 1.83 g(51.9%) of a light-yellow oil.

[0272] 3-((3S)-3-Pyrrolidinyloxy)pyridine

[0273] Under a nitrogen atmosphere, a cold (0-5° C.), stirring solutionof 3-((3S)-N-(tert-butoxycarbonyl)-3-pyrrolidinyloxy)pyridine (0.535 g,2.024 mmol) in dry CH₂Cl₂ (5 mL, distilled from LiAlH₄) was treateddrop-wise with trifluoroacetic acid (3 mL, 4.44 g, 38.94 mmol). Afterstirring 30 min at 0-5° C., the solution was concentrated by rotaryevaporation. The residue was acidified with 1 M HCl solution (15 mL) andextracted with toluene (4×25 mL) to remove impurities(triphenylphosphine oxide). At 0-5° C., the aqueous layer was basifiedwith 1 M NaOH solution to pH 12. The mixture was saturated with NaCl andextracted with CHCl₃ (8×20 mL). The combined CHCl₃ extracts were dried(Na₂SO₄), filtered, concentrated by rotary evaporation and briefly driedunder high vacuum to give 240 mg (72.3%) of a light-yellow oil.

[0274] 3-((3S)-3-Pyrrolidinyloxy)pyridine Dihydrochloride

[0275] Concentrated HCl (2 mL) was added drop-wise to3-((3S)-3-pyrrolidinyloxy)pyridine (240 mg, 1.462 mmol), and theresulting solution was concentrated by rotary evaporation. Ethanol wasadded to the residue and removed by rotary evaporation to dry theproduct. The procedure was repeated several times until a solid wasobtained. Ethanol (1 mL) was added, and the resulting solution wastreated with hot 2-propanol producing a precipitate. The solution wasallowed to cool to ambient temperature and was further cooled at 5° C.for 48 h. The solids were filtered and dried under vacuum at 40° C. for16 h to afford 215 mg (62.0%) of a hygroscopic, light-brown, granularsolid, mp 145-148° C., [α]^(20.5)D+26.67° (c 1.0, MeOH). The compoundexhibits a Ki of 230 nM.

Example 37 Synthesis of 3-(1-Methyl-4-piperidinyloxy)pyridine

[0276] 3-(1-Methyl-4-piperidinyloxy)pyridine

[0277] Under a nitrogen atmosphere, a solution of diethylazodicarboxylate (6.80 g. 39.0 mmol) in tetrahydrofuran (THF) (25 mL)was added drop-wise at ambient temperature to a stirring solution oftriphenylphosphine (10.23 g, 390 mmol) in THF (100 mL). The resultingsolution was allowed to stir at ambient temperature for 30 min.4-Hydroxy-1-methylpiperidine (3.05 g, 26.5 mmol) and 3-hydroxypyridine(3.71 g, 39.0 mmol) were added, and the reaction mixture was stirred atambient temperature for 18 h. The solution was concentrated by rotaryevaporation, and the resulting residue was dissolved in CHCl₃ (100 mL).The suspension was cooled in an ice-water bath, and a solution of 1 MHCl (75 mL) was added with stirring. The aqueous phase was separated.The organic phase was extracted with water (3×75 mL). The combinedaqueous extracts were cooled in an ice-water bath, basified with 1 MNaOH solution (125 mL) to pH˜11 and extracted with CHCl₃ (6×50 mL). Thecombined organic extracts were dried (Na₂SO₄), filtered, andconcentrated by rotary evaporation. The crude product was dissolved inCHCl₃ (75 mL), and the CHCl₃ solution was extracted with 1 M NaOHsolution (4×25 mL) to remove residual 3-hydroxypyridine. The CHCl₃ phasewas separated, and the combined NaOH layers were back extracted withCHCl₃ (3×50 mL). All CHCl₃ extracts were combined, dried (Na₂SO₄),filtered, and concentrated by rotary evaporation. The resulting oil waspurified by vacuum distillation using a test-tube distillationapparatus, collecting the fraction with bp 83-93° C. at 0.10-0.075 mmHg. Further purification by a second vacuum distillation yielded 120 mg(2.4%) of a colorless oil, bp 72-75° C. at 0.75 mm Hg. The compoundexhibits a Ki of 4897 nM.

Example 38 Synthesis of (2-(5-Bromo(3-pyridylthio))ethyl)methylamine

[0278] 2-(5-Bromo-3-pyridylthio)ethan-1-ol

[0279] Under a nitrogen atmosphere, a mixture of 2-mercaptoethanol (3.30g, 42.21 mmol), sodium hydroxide (1.69 g, 42.21 mmol) andN,N-dimethylformamide (50 mL) was stirred at ambient temperature for 4h. The resulting solution was cooled to 0-5° C. and 3,5-dibromopyridine(8.00 g, 33.77 mmol) was added in one portion. The mixture was stirredat 0-5° C. for 20 min, warmed to ambient temperature and further stirredfor 1 h. TLC analysis on silica gel eluting with EtOAc-hexane (3:1)indicated an incomplete reaction. Therefore, the mixture was heated at75° C. (oil bath temperature) for 17 h. After cooling to ambienttemperature, the mixture was poured into water (250 mL) and extractedwith ether (3×75 mL). The combined ether extracts were dried (Na₂SO₄),filtered and concentrated (rotary evaporator) to a light-yellow oil. Theoil was vacuum distilled using a short-path distillation apparatus toafford 4.55 g (57.5%) of a light-yellow oil, bp 138-140° C. at 0.35 mmHg.

[0280] (2-(5-Bromo(3-pyridylthio))ethyl)methylamine

[0281] Under a nitrogen atmosphere, a cold (0-5° C.), stirring solutionof 2-(5-bromo-3-pyridylthio)ethan-1-ol (1.00 g, 4.27 mmol) indichloromethane (4 mL) containing pyridine (3 drops) was treated in oneportion with p-toluenesulfonyl chloride (0.855 g, 4.49 mmol). Theresulting solution was allowed to warm to ambient temperature over 16 h.The solution was concentrated on a rotary evaporator, and the oilyresidue was dried under high vacuum to give a light-beige solid. Thesolid was partitioned between saturated K₂CO₃ solution (12 mL) and CHCl₃(10 mL). The CHCl₃ phase was separated and the aqueous phase wasextracted with CHCl₃ (3×10 mL). All CHCl₃ extracts were combined andwashed with saturated NaCl solution (10 mL). The CHCl₃ extracts wereconcentrated (rotary evaporator) to an oil that was dried under highvacuum to yield a light beige solid (1.83 g). The solid was transferredto a heavy-walled glass pressure-tube apparatus with methanol (10 mL),and a 40 wt % aqueous solution of methylamine (26 mL) was added. Thetube was sealed and the mixture was stirred and heated at 115° C. (oilbath temperature) for 45 min. The resulting solution was allowed to coolto ambient temperature and was further stirred for 16 h. The solutionwas concentrated on a rotary evaporator. The resulting oil was basifiedwith 1 M NaOH solution (10 mL) and extracted with CHCl₃ (4×10 mL). Thecombined CHCl₃ extracts were washed with saturated NaCl solution (10mL), dried (Na₂SO₄), filtered and concentrated to a brown oil (1.22 g).The crude product was purified by column chromatography on silica gel(50 g), eluting with EtOAc-hexane (3:1, v/v) to collect2-(5-bromo-3-pyridylthio)ethan-1-ol (R_(f) 0.25) (0.47 g). Furtherelution with MeOH-Et₃N (97:3, v/v) afforded 0.38 g (35.6%) of(2-(5-bromo(3-pyridylthio))ethyl)methylamine (R_(f) 0.49) as alight-yellow oil.

[0282] (2-(5-Bromo(3-pyridylthio))ethyl)methylamine Hemigalactarate

[0283] To a solution of (2-(5-bromo(3-pyridylthio))ethyl)methylamine(352.3 mg, 1.43 mmol) in ethanol (5 mL) was added galactaric acid (150.0mg, 0.71 mmol). Water (2 mL) was added drop-wise, while gently warmingthe solution. To remove some white, insoluble crystals, the warmsolution was filtered through a glass wool plug, washing the filter plugwith a warm solution of ethanol-water (4:1, v/v) (2 mL). The filtratewas diluted with ethanol (9.5 mL), producing a white precipitate. Themixture was allowed to cool to ambient temperature and was furthercooled at 5° C. for 48 h. The precipitate was filtered, washed withethanol (4 mL) and vacuum dried at 45° C. for 18 h to give 437.5 mg(87.2%) of a white, crystalline powder, mp 161.5-166° C. (d). Thecompound exhibits a Ki of 3400 nM.

Example 39 Synthesis of(2-(5-Bromo(3-pyridylthio))-isopropyl)methylamine Hemigalactarate and(2-(5-Bromo(3-pyridylthio))propyl)methylamine Hemigalactarate

[0284] 1-(5-Bromo-3-pyridylthio)propan-2-ol

[0285] Under a nitrogen atmosphere, a mixture of 1-mercapto-2-propanol(3.89 g, 42.21 mmol), sodium hydroxide (1.69 g, 42.21 mmol) andN,N-dimethylformamide (DMF) (40 mL) was heated at 105° C. (oil bathtemperature) for 2 h. The resulting solution was cooled to ambienttemperature and 3,5-dibromopyridine (8.00 g, 33.77 mmol) was added inone portion using additional DMF (10 mL). The mixture was stirred atambient temperature for 48 h. The turbid mixture was then heated undernitrogen at 85° C. (oil bath temperature) for 18 h. The mixture wascooled to ambient temperature, diluted with water (250 mL) and extractedwith ether (3×75 mL). The combined ether extracts were washed withsaturated NaCl solution (100 mL), dried (Na₂SO₄), filtered andconcentrated to a light-yellow foam (9.19 g). The crude product waspurified by column chromatography on silica gel (225 g), eluting withEtOAc-hexane (3:1, v/v). Fractions containing the product (R_(f) 0.38)were combined and concentrated to give 3.78 g (45.1%) of a light-yellowoil.

[0286] (2-(5-Bromo(3-pyridylthio))-isopropyl)methylamine and(2-(5-Bromo(3-pyridylthio))propyl)methylamine

[0287] Under a nitrogen atmosphere, a cold (0-5° C.), stirring solutionof 1-(5-bromo-3-pyridylthio)propan-2-ol (1.80 g, 7.25 mmol) indichloromethane (8 mL) containing pyridine (3 drops) was treated in oneportion with p-toluenesulfonyl chloride (1.452 g, 7.07 mmol). Theresulting solution was allowed to warm to ambient temperature over 16 h.TLC analysis on silica gel eluting with EtOAc-hexane (3:1, v/v)indicated an incomplete reaction. Therefore, additionalp-toluenesulfonyl chloride (0.28 g, 1.45 mmol), triethylamine (1 mL) andpyridine (1 mL) were added. The mixture was allowed to stir undernitrogen for 48 h. The solution was concentrated on a rotary evaporatorto a red oil. The oil was cooled to 0-5° C., basified with saturatedK₂CO₃ solution (40 mL) and extracted with CH₂Cl₂ (3×25 mL). The combinedCH₂Cl₂ extracts were washed with saturated NaCl solution (50 mL), dried(Na₂SO₄), filtered, concentrated (rotary evaporator, using toluene (3×20mL) to azeotropically remove pyridine) and further dried under highvacuum to afford a dark-red oil (2.65 g). The oil was dissolved inmethanol (20 mL) and transferred to a heavy-walled glass pressure-tubeapparatus. A 40 wt % aqueous solution of methylamine (80 mL) was added.The tube was sealed and the mixture was stirred and heated at 1 20° C.for 2.5 h. The resulting brown solution was allowed to cool to ambienttemperature and was further stirred for 16 h. The solution wasconcentrated to a dark-brown oil. At 0-5° C., the oil was basified with1 M NaOH solution (20 mL) and extracted with CHCl₃ (6×20 mL). Thecombined CHCl₃ extracts were washed with saturated NaCl solution (10mL), dried (Na₂SO₄), filtered, concentrated and further dried under highvacuum to yield a brown oil (1.56 g).

[0288] The crude product was purified by column chromatography on silicagel (80 g), eluting with EtOAc-hexane (3:1, v/v) to collect1-(5-bromo-3-pyridylthio)propan-2-ol (R_(f) 0.38) (0.05 g). Furtherelution with MeOH-Et₃N (97:3, v/v) afforded a brown oil (R_(f) 0.58).The oil was dissolved in CHCl₃. The CHCl₃ solution was dried (Na₂SO₄),filtered, concentrated and further dried under high vacuum to yield 1.01g of (2-(5-bromo(3-pyridylthio))-isopropyl)methylamine and(2-(5-bromo(3-pyridylthio))propyl)methylamine as a 56:38 mixture,respectively. The mixture was used without further purification.

[0289] (2-(5-Bromo(3-pyridylthio))-isopropyl)methylamine Hemigalactarateand (2-(5-Bromo(3-pyridylthio))propyl)methylamine Hemigalactarate

[0290] A hot solution of the mixture of(2-(5-bromo(3-pyridylthio))-isopropyl)methylamine and(2-(5-bromo(3-pyridylthio))propyl)methylamine (1.01 g, 3.867 mmol) inethanol (15 mL) was treated in one portion with galactaric acid (0.406g, 1.937 mmol). Water (3 mL) was added drop-wise, while warming thesolution to reflux. To remove some white, insoluble solids, the warmsolution was filtered through a glass wool plug, washing the filter plugwith a warm solution of ethanol-water (4:1, v/v) (5 mL). The filtratewas diluted with ethanol (22.5 mL). The mixture was allowed to cool toambient temperature and was allowed to stand for 16 h. The resultingsolids were filtered, washed with ethanol (2×5 mL), and vacuum dried at45° C. to give 0.512 g (36.1%) of light-beige, crystalline flakes, mp146.5-149.5° C. Analysis indicated a 57:41 mixture of(2-(5-bromo(3-pyridylthio))-isopropyl)methylamine hemigal actarate and(2-(5-bromo(3-pyridylthio))-propyl)methylamine hemigalactarate. Thecompound exhibits a Ki of 5500 nM.

Example 40 Synthesis of 3-(5-Bromo-3-pyridylthio))propyl)methylamineHemigalactarate

[0291] 3-(5-Bromo-3-pyridylthio)propan-1-ol

[0292] Under a nitrogen atmosphere, a mixture of 3-mercapto-1-propanol(3.89 g, 42.21 mmol), sodium hydroxide (1.69 g, 42.21 mmol) andN,N-dimethylformamide (DMF) (40 mL) was heated at 45° C. (oil bathtemperature) for 4 h. The resulting solution was cooled to ambienttemperature and 3,5-dibromopyridine (8.00 g, 33.77 mmol) was added inone portion. The mixture was stirred and heated at 55° C. (oil bathtemperature) for 60 h. The mixture was cooled to ambient temperature,diluted with water (250 mL), treated with saturated NaCl solution andextracted with ether (4×75 mL). The combined ether extracts were washedwith saturated NaCl solution (100 mL), dried (Na₂SO₄), filtered andconcentrated. The residue was dried under high vacuum to give alight-yellow oil (8.25 g). The crude product was purified by vacuumdistillation to afford 6.79 g (81.0%) of a very pale-yellow oil, bp148-152° C. at 0.5 mm Hg.

[0293] 3-(5-Bromo-3-pyridylthio))propyl)methylamine

[0294] Under a nitrogen atmosphere, a cold (0-5° C.), stirring solutionof 3-(5-bromo-3-pyridylthio)propan-1-ol (6.64 g, 26.77 mmol) indichloromethane (35 mL) and triethylamine (35 mL) was treated in oneportion with p-toluenesulfonyl chloride (5.36 g, 28.11 mmol). Theresulting solution was allowed to warm to ambient temperature and wasfurther stirred for 48 h. The solution was concentrated on a rotaryevaporator. The residue was basified at 0-5° C. with saturated K₂CO₃solution (75 mL) and extracted with CH₂Cl₂ (4×10 mL). The combinedCH₂Cl₂ extracts were washed with saturated NaCl solution (100 mL), dried(Na₂SO₄), filtered and concentrated (rotary evaporator) to a dark redoil (10.22 g). The oil was transferred to a heavy-walled glasspressure-tube apparatus with methanol (25 mL), and a 40 wt % aqueoussolution of methylamine (100 mL) was added. The tube was sealed and themixture was stirred and heated at 120° C. (oil bath temperature) for 2h. The resulting solution was allowed to cool to ambient temperature andwas further stirred for 16 h. The solution was concentrated on a rotaryevaporator. The resulting oil was basified with 1 M NaOH solution (30mL) and extracted with CHCl₃ (5×30 mL). The combined CHCl₃ extracts werewashed with saturated NaCl solution (50 mL), dried (Na₂SO₄), filteredand concentrated to a brown oil. The crude product was purified bycolumn chromatography on silica gel (190 g), eluting with EtOAc-hexane(3:1, v/v) to collect 3-(5-bromo-3-pyridylthio)propan-1-ol (R_(f) 0.40)(0.46 g). Further elution with MeOH-Et₃N (97:3, v/v) afforded 4.52 g(64.6%) of 3-(5-bromo-3-pyridylthio))propyl)methylamine (R_(f) 0.27) asa light-yellow oil.

[0295] 3-(5-Bromo-3-pyridylthio))propyl)methylamine Hemigalactarate

[0296] A hot solution of 3-(5-bromo-3-pyridylthio))propyl)methylamine(1.00 g, 3.828 mmol) in ethanol (15 mL) was treated in one portion withgalactaric acid (0.402 g, 1.914 mmol). Water (3 mL) was added drop-wise,while warming the solution to reflux. To remove some white, insolublesolids, the warm solution was filtered through a glass wool plug,washing the filter plug with a warm solution of ethanol-water (4:1, v/v)(5 mL). The filtrate was diluted with ethanol (22.5 mL). The mixture wasallowed to cool to ambient temperature and was further cooled at 5° C.for 16 h. The resulting solids were filtered, washed with ethanol (5mL), and vacuum dried at 40° C. to give 1.28 g (91.3%) of an off-white,crystalline powder, mp 152.5-154.5° C. The compound exhibits a Ki of39950 nM.

[0297] The foregoing is illustrative of the present invention and is notto be construed as limiting thereof. The invention is defined by thefollowing claims, with equivalents of the claims to be included therein.

That which is claimed is:
 1. A compound of the formula:

where X is nitrogen or carbon bonded to a substituent speciescharacterized as having a sigma m value between about −0.3 and about0.75; X′ is nitrogen or carbon bonded to a substituent speciescharacterized as having a sigma m value between about −0.3 and about0.75, but not equal to 0; m is an integer and n is an integer such thatthe sum of m plus n is 1, 2, 3, 4, 5, 6, 7, or 8; Z′ and Z″ individuallyrepresent hydrogen or lower alkyl; E, E′, E″ and E′″ individuallyrepresent hydrogen or a non-hydrogen substituent; A, A′ or A″ areindividually hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl,arylalkyl and substituted arylalkyl functionalities; and B′ is oxygen.2. The compound of claim 1 , wherein X′ is C—NR′R″, C—OR′ or C-NO₂wherein R′ and R″ are selected from the group consisting of hydrogen,lower alkyl, aromatic group containing species and substitutedaromatic-group containing species.
 3. The compound of claim 1 wherein X′is C—NH₂, C—NHCH₂ or C—N (CH₃)₂.
 4. The compound of claim 1 wherein 0, 1or 2 of the substituents designated as E, E′, E″ and E′″ arenon-hydrogen substituents.
 5. The compound of claim 1 wherein X′ isnitrogen.
 6. The compound of claim 1 wherein X is CH, CBr or COR.
 7. Thecompound of claim 1 wherein A, A′ and A″ are all hydrogen.
 8. Thecompound of claim 1 wherein E, E′, E″ and E′″ individually are hydrogenor lower alkyl.
 9. The compound of claim 1 , wherein at least one of Z′and Z″ are hydrogen.
 10. The compound of claim 9 wherein Z′ is hydrogenand Z″ is methyl.
 11. The compound of claim 1 , selected from the groupconsisting of 2-(3-pyridyloxy)ethylamine,methyl(2-(3-pyridyloxy)ethyl)amine, dimethyl(2-(3-pyridyloxy)ethylamine,dimethyl(4-(3-pyridyloxy)butyl)amine,methyl(4-(3-pyridyloxy)butyl)amine,(3-(5-chloro(3-pyridyloxy))-1-methylpropyl)methylamine,methyl(3-(5-(phenylmethoxy) (3-pyridyloxy))propyl)amine,(3-(5-chloro(3-pyridyloxy))propyl) methylamine ,methyl(3-(6-methyl(3-pyridyloxy))propyl)amine,methyl(3-(2-methyl(3-pyridyloxy))propyl)amine, cyclopropyl(3-(3-pyridyloxy)propyl)amine, 3-(5-chloro-3-pyridyloxy)propylamine,methyl(3-(5-methoxy-3-pyridyloxy)propyl)amine,ethyl(3-(3-pyridyloxy)propyl)amine, methyl(3-(5-isopropoxy-3-pyridyloxy)propyl)amine, (methylethyl)(3-(3-pyridyloxy)propyl) amine,methyl(1-methyl-3-(3-pyridyloxy)propyl)amine,(3-(3-aminophenoxy)propyl)methylamine,methyl(3-(3-nitrophenoxy)propyl)amine, 3-(3-pyridyloxy)propylamine,1-(3-chloropropoxy)-3-nitrobenzene, benzyl(3-(3-pyridyloxy)propyl)amine,dimethyl(3-(3-(methylamino)propoxy)phenyl)amine, anddimethyl(3-(3-pyridyloxy)propyl)amine.
 12. A method of treating acentral nervous system disorder comprising administering to a subject inneed thereof, an effective amount of a compound of the formula:

where X is nitrogen or carbon bonded to a substituent speciescharacterized as having a sigma m value between about −0.3 and about0.75; X′ are individually nitrogen, N—O or carbon bonded to asubstituent species characterized as having a sigma m value betweenabout −0.3 and about 0.75; m is an integer and n is an integer such thatthe sum of m plus n is 1, 2, 3, 4, 5, 6, 7, or 8; Z′ and Z″ individuallyrepresent hydrogen or lower alkyl; E, E′, E″ and E′″ individuallyrepresent hydrogen or a non-hydrogen substituent; or E and E′ or E″ andE′″ and their associated carbon atom combine to form a ring structure;or E′″ and E′, when located on immediately adjacent carbon atoms, andtheir associated carbon atoms combine to form a ring structure; A, A′ orA″ are individually hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substitutedalkylaryl, arylalkyl and substituted arylalkyl functionalities; oradjacent substituents of A, A′ or A″, when X or X′ are carbon bonded toa substituent component, combine to form one or more saturated orunsaturated, carboxycyclic or heterocyclic rings; and B′ is oxygen. 13.The method of claim 12 , whereby X′ is C—NR′R″, C—OR′ or C—NO₂ whereinR′ and R″ are selected from the group consisting of hydrogen, loweralkyl, aromatic group containing species and substituted aromatic-groupcontaining species.
 14. The method of claim 12 , whereby X′ is C—NH₂,C—NHCH₂ or C—N(CH₃)₂.
 15. The method of claim 12 , whereby zero, one ortwo of the substituents designated as E, E′, E″ and E′″ are non-hydrogensubstituents.
 16. The method of claim 12 , whereby X′ is nitrogen. 17.The method of claim 12 , whereby X is CH, CBr or COR.
 18. The method ofclaim 12 , whereby A, A′ and A″ are all hydrogen.
 19. The method ofclaim 12 , whereby E, E′, E″ and E′″ individually are hydrogen or loweralkyl.
 20. The method of claim 19 , whereby at least one of Z′ and Z″are hydrogen.
 21. The method of claim 12 , whereby Z′ is hydrogen and Z″is methyl.
 22. The method of claim 12 , whereby the compound is selectedfrom the group consisting of 2-(3-pyridyloxy)ethylamine,methyl(2-(3-pyridyloxy)ethyl)amine, dimethyl(2-(3-pyridyloxy)ethylamine,dimethyl(4-(3-pyridyloxy)butyl)amine,methyl(4-(3-pyridyloxy)butyl)amine,(3-(5-chloro(3-pyridyloxy))-1-methylpropyl)methylamine,methyl(3-(5-(phenyl methoxy)(3-pyridyloxy))propyl)amine,(3-(5-chloro(3-pyridyloxy))propyl)methylamine,methyl(3-(6-methyl(3-pyridyloxy))propyl)amine, methyl(3-(2-methyl(3-pyridyloxy))propyl)amine, cyclopropyl(3-(3-pyridyloxy)propyl)amine,3-(5-chloro-3-pyridyloxy)propylamine,methyl(3-(5-methoxy-3-pyridyloxy)propyl)amine,ethyl(3-(3-pyridyloxy)propyl)amine,methyl(3-(5-isopropoxy-3-pyridyloxy)propyl)amine,(methylethyl)(3-(3-pyridyloxy)propyl)amine,methyl(1-methyl-3-(3-pyridyloxy)propyl)amine,(3-(3-aminophenoxy)propyl)methylamine,methyl(3-(3-nitrophenoxy)propyl)amine, 3-(3-pyridyloxy)propylamine,1-(3-chloropropoxy)-3-nitrobenzene, benzyl(3-(3-pyridyloxy)propyl)amine,dimethyl(3-(3-(methylamino)propoxy)phenyl)amine, anddimethyl(3-(3-pyridyloxy)propyl)amine.
 23. A pharmaceutical compositionincorporating a compound of the formula:

where X is nitrogen or carbon bonded to a substituent speciescharacterized as having a sigma m value between about −0.3 and about0.75; X′ are individually nitrogen, N—O or carbon bonded to asubstituent species characterized as having a sigma m value betweenabout −0.3 and about 0.75; m is an integer and n is an integer such thatthe sum of m plus n is 1, 2, 3, 4, 5, 6, 7, or 8; Z′ and Z″ individuallyrepresent hydrogen or lower alkyl; E, E′, E″ and E′″ individuallyrepresent hydrogen or a non-hydrogen substituent; or E and E′ or E″ andE′″ and their associated carbon atom combine to form a ring structure;or E′″ and E′, when located on immediately adjacent carbon atoms, andtheir associated carbon atoms combine to form a ring structure; A, A′ orA″ are individually hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substitutedalkylaryl, arylalkyl and substituted arylalkyl functionalities; oradjacent substituents of A, A′ or A″, when X or X′ are carbon bonded toa substituent component, combine to form one or more saturated orunsaturated, carbocyclic or heterocyclic rings; and B′ is oxygen. 24.The pharmaceutical composition of claim 23 , wherein X′ is C—NR′R″,C—OR′ or C—NO₂ wherein R′ and R″ are selected from the group consistingof hydrogen, lower alkyl, aromatic group containing species andsubstituted aromatic group containing species.
 25. The pharmaceuticalcomposition of claim 23 , wherein X′ is C—NH₂, C—N HCH₂ or C—N(CH₃)₂.26. The pharmaceutical composition of claim 23 , wherein zero, one ortwo of the substituents designated as E, E′, E″ and E′″ are non-hydrogensubstituents.
 25. The pharmaceutical composition of claim 23 , whereinX′ is nitrogen.
 26. The pharmaceutical composition of claim 23 , whereinX is CH, CBr or COR.
 27. The pharmaceutical composition of claim 23 ,wherein A, A′ and A″ are all hydrogen.
 28. The pharmaceuticalcomposition of claim 23 , wherein E, E′, E″ and E′″ individually arehydrogen or lower alkyl.
 29. The pharmaceutical composition of claim 28, wherein at least one of Z′ and Z″ are hydrogen.
 30. The pharmaceuticalcomposition of claim 23 wherein Z′ is hydrogen and Z″ is methyl.
 31. Thepharmaceutical composition of claim 23 , wherein the compound isselected from the groups consisting of 2-(3-pyridyloxy)ethylamine,methyl(2-(3-pyridyloxy)ethyl)amine, dimethyl(2-(3-pyridyloxy)ethylamine,dimethyl(4-(3-pyridyloxy)butyl)amine,methyl(4-(3-pyridyloxy)butyl)amine,(3-(5-chloro(3-pyridyloxy))-1-methylpropyl)methylamine,methyl(3-(5-(phenylmethoxy)(3-pyridyloxy))propyl)amine,(3-(5-chloro(3-pyridyloxy))propyl)methylamine,methyl(3-(6-methyl(3-pyridyloxy))propyl)amine,methyl(3-(2-methyl(3-pyridyloxy))propyl)amine,cyclopropyl(3-(3-pyridyloxy)propyl)amine,3-(5-chloro-3-pyridyloxy)propylamine,methyl(3-(5-methoxy-3-pyridyloxy)propyl)amine,ethyl(3-(3-pyridyloxy)propyl)amine,methyl(3-(5-isopropoxy-3-pyridyloxy)propyl)amine,(methylethyl)(3-(3-pyridyloxy)propyl)amine,methyl(1-methyl-3-(3-pyridyloxy)propyl)amine,(3-(3-aminophenoxy)propyl)methylamine,methyl(3-(3-nitrophenoxy)propyl)amine, 3-(3-pyridyloxy)propylamine,1-(3-chloropropoxy)-3-nitrobenzene, benzyl(3-(3-pyridyloxy)propyl)amine,dimethyl(3-(3-(methylamino)propoxy)phenyl)amine, anddimethyl(3-(3-pyridyloxy)propyl)amine.